NIAID conducts and supports research to prevent, diagnose, and treat infectious and immunological diseases that affect the health of women and girls.
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HIV/AIDSImmunologyInfectious Diseases (Other Than HIV/AIDS)
In the United States, 10 to 30 percent of HIV-positive individuals are also infected with hepatitis C virus (HCV). Liver-related disease and death from chronic HCV infection remains a significant problem in people co-infected with HIV. Previous studies show that African American women co-infected with HIV and HCV are 60 percent less likely to die from liver-related disease than co-infected Hispanic or Caucasian women. However, the basis for these disparities is not known. To look for genetic factors that might explain these racial/ethnic differences, NIAID-funded scientists studied participants in the Women’s Interagency HIV Study (WIHS), a multicenter cohort of women at risk for or currently diagnosed with HIV. They investigated whether the differences in liver-related mortality were linked with common genetic variants in and around the IFNL2 and IFNL4 genes—two related genes that are associated with HCV and the response to antiviral drugs. The analysis showed that two genetic variants were associated with increased mortality due to HCV. However, these differences did not explain the lower risk of death among African American HIV/HCV co-infected women, suggesting that other genetic, behavioral, and/or environmental factors may contribute to racial/ethnic differences in liver-related mortality.
Reference: Sarkar M et al. Association of IFNL3 and IFNL4 polymorphisms with liver-related mortality in a multiracial cohort of HIV/HCV-coinfected women. J Viral Hepat. 2015 Dec;22(12):1055-60.
HIV superinfection occurs when a person with HIV is infected with a new strain of HIV. HIV superinfection can increase viral load (blood levels of HIV) and the risk of HIV transmission to other people. To examine whether maternal HIV superinfection affects the risk of mother-to-child transmission (MTCT) of HIV through breastfeeding, NIAID intramural researchers performed a follow-up analysis on participants who were originally enrolled in the Post-Exposure Prophylaxis of Infants trial in Malawi. Ten of the 182 study participants acquired HIV superinfection after giving birth (postpartum), and five of these superinfected mothers transmitted HIV to their infants. Maternal HIV superinfection did not increase the odds of MTCT of HIV via breastfeeding when the researchers considered maternal age, baseline CD4 cell count, and baseline viral load. Longer breastfeeding duration was associated with a lower risk of HIV superinfection. The researchers concluded that the high rates of superinfection observed in this study support the use of antiretroviral therapy during pregnancy and for a lifetime thereafter, as it is likely to reduce the risk of MTCT and potential adverse effects of HIV superinfection, such as higher viral loads.
Reference: Redd AD et al. Evaluation of postpartum HIV superinfection and mother-to-child transmission. AIDS. 2015 Jul 31;29(12):1567-73.
HIV infection is associated with osteoporosis—a reduction of bone mineral density (BMD) that leaves bones vulnerable to breaking under mild stress, such as coughing or bending over. In people over 50, women are four times more likely than men to have osteoporosis. The contribution of untreated HIV infection to BMD loss is unclear. NIAID-funded investigators examined the association of traditional osteoporosis risk factors and HIV parameters with BMD at the hip and spine in HIV-infected adults who had normal CD4 cell counts and had not undergone antiretroviral therapy (ART). The Strategic Timing of Antiretroviral Treatment (START) Bone Mineral Density Substudy involved 424 ethnically diverse participants in 11 countries. Although osteoporosis among the participants was rare (1.9 percent), low BMD was common (35.1 percent). A longer duration of HIV infection (time since HIV diagnosis) was associated with lower BMD at the hip but not the spine. The scientists found that low BMD was associated with traditional risk factors such as female sex and older age but not with CD4 cell count or viral load, which are markers of HIV/AIDS severity. This is the first study to evaluate BMD in HIV-infected adults who have not received ART across more than one region.
Reference: Carr A et al. Prevalence of and risk factors for low bone mineral density in untreated HIV infection: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial. HIV Med. 2015 Apr;16 Suppl 1:137-46.
Access to safe and effective contraception that does not interfere with the efficacy of antiretroviral therapy (ART) is a critical need for women living with HIV. Interactions between ART and contraceptives could decrease the efficacy of one or both therapies or increase side effects. Developing countries have both a high prevalence of women with HIV and a high level of use of the long-acting hormonal contraceptive depot medroxyprogesterone acetate (DMPA). Both DMPA and the commonly used ART regimen consisting of a combination of lopinavir and ritonavir (LPV/r) are metabolized in the liver through the cytochrome P450 (CYP) system of enzymes. Furthermore, ritonavir inhibits a CYP enzyme, CYP3A4, which is more active in women. NIAID-funded researchers investigated potential interactions between LPV/r and DMPA in premenopausal HIV-infected women by examining the blood levels of the drugs, their metabolites (breakdown products), and HIV RNA. They found no difference in the levels of ART drugs and effective control of HIV for those who adhered to their ART regimen. Levels of MPA, the active metabolite of DMPA, were elevated compared with levels in HIV-infected women (from an earlier study) who took DMPA but did not take ART or took a different type of ART. However, ovulation was suppressed and no unusual side effects were reported. This study demonstrates that the concurrent use of LPV/r and DMPA is safe and effective for HIV-infected women.
Reference: Luque AE et al. Depot medroxyprogesterone acetate in combination with a twice-daily lopinavir-ritonavir-based regimen in HIV-infected women showed effective contraception and a lack of clinically significant interactions, with good safety and tolerability: results of the ACTG 5283 study. Antimicrob Agents Chemother. 2015 Apr;59(4):2094-101.
The first-line HIV therapy atazanavir is commonly used as one of the medications in combination antiretroviral drug regimens because it is a potent, once-daily drug that patients tolerate well. Prior studies have shown sex-related variability in blood concentrations of atazanavir. However, how the body processes the drug over time and the resulting clinical implications had not been determined. NIAID-funded researchers studied atazanavir concentration in the blood of 131 women and 655 men infected with HIV. They found that women cleared atazanavir from their bloodstream 14 percent more slowly than men did, after accounting for differences in body weight. In addition, women with fast clearance of atazanavir and men with slow clearance had worse clinical outcomes, including an inability to tolerate atazanavir and failure to suppress HIV. These outcomes occurred despite patients’ adherence to atazanavir treatment. This study showed that a patient’s sex is an important factor in atazanavir clearance and treatment outcomes.
Reference: Venuto CS et al. Sex differences in atazanavir pharmacokinetics and associations with time to clinical events: AIDS Clinical Trials Group Study A5202. J Antimicrob Chemother. 2014 Dec;69(12):3300-10.
The VOICE study, a randomized clinical trial of more than 5,000 reproductive-age women conducted at multiple sites in South Africa, Uganda, and Zimbabwe, was designed to evaluate the safety and effectiveness of three pre-exposure prophylaxis (PrEP) approaches in preventing male-to-female HIV transmission. The approaches tested were tenofovir 1 percent vaginal gel and oral tablets containing either the antiretroviral drug tenofovir or a combination of tenofovir and another antiretroviral drug, emtricitabine. Final study results showed that, compared with placebo, none of the drug regimens reduced the rate of HIV infection. Most study participants did not use the study products daily and this could explain the results. However, the researchers were not able to rule out differences in exposure to HIV between women who used the study products and those who did not. While the study was underway, FDA approved PrEP for HIV prevention in high-risk individuals. Nonetheless, these results reaffirm the need for effective and acceptable prevention methods for women who are at high risk for sexual acquisition of HIV and suggest that measures that are more accurate are critical for estimating product use during HIV prevention trials.
Reference: Marrazzo JM et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015 Feb 5;372(6):509-18.
Women represent the majority of HIV-infected individuals worldwide. Although several studies have reported cognitive impairment in women infected with HIV, the sample sizes of previous studies were too small to understand the factors that may affect cognitive function in these women. As part of the Women’s Interagency HIV Study (WIHS), the largest and longest-running study to investigate the impact of HIV on U.S. women, NIAID-funded researchers studied cognitive function in American, urban-dwelling women. To distinguish the effects of HIV versus other factors that could affect cognitive function, the researchers studied socially and demographically similar women who were either HIV-infected (1,019 participants) or uninfected (502 participants). The study participants completed eight different cognitive tests during four semi-annual WIHS visits. The results showed that HIV infection had a very small but significant effect on cognition: HIV-infected women performed worse than uninfected women on tests of verbal learning, delayed recall and recognition, attention, and psychomotor speed (coordinating thinking and physical movement). The factor most strongly associated with cognitive deficit in HIV-infected women was low reading level. HIV-infected women with low education or compromised immune functions were most vulnerable to cognitive deficits. Results of this study will help define how best to treat HIV-infected women in the United States and globally.
Reference: Maki PM et al. Cognitive function in women with HIV: findings from the Women's Interagency HIV Study. Neurology. 2015 Jan 20;84(3):231-40.
In children, severe asthma is more prevalent in boys than in girls, but after puberty, women are twice as likely as men to have severe asthma. These observations suggest that sex hormones play a role in the disease process. Researchers funded by NIAID investigated the role of female hormones in regulating the production of interleukin (IL)-17A, an immune system protein that mediates inflammation in the lungs and respiratory airways and is associated with severe asthma.
Researchers found that in both healthy adults and adults with severe asthma, the production of IL-17A by specialized immune cells called TH17 cells was increased in women compared with men. This increased production of IL-17A by TH17 cells appears to be mediated by an increase in the levels of IL-23R, a receptor important for TH17 cell function and IL-17A production, and a decrease in levels of let-7f microRNA, a molecule known to inhibit IL-17A production. Follow-up experiments in mice showed that exposure to a combination of two female hormones, estradiol (estrogen) and progesterone, increased IL-17A production by reducing let-7f expression and increasing IL-23R expression. Additional studies showed that activated TH17 cells from female mice, but not from male mice, could trigger the infiltration of lung tissue by white blood cells called neutrophils, as occurs in people with severe asthma. Together, these results provide a plausible mechanism for the increased prevalence of severe asthma in women compared with men and could ultimately lead to new treatments.
Reference: Newcomb DC. Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL-23 receptor signaling and IL-17A production in patients with severe asthma. J Allergy Clin Immunol. 2015 Oct;136(4):1025-1034.e11.
Systemic lupus erythematosus (SLE or lupus) is a relapsing autoimmune disease that most often affects women of childbearing age. People with SLE have high serum levels of autoantibodies—antibodies that react against the body’s own cells and tissues. These autoantibodies are continuously present in SLE, but the levels of some autoantibodies, and of antibody-secreting B cells, increase in patients suffering a relapse, or “flare,” of the disease. Until now, the origins and properties of antibody-secreting cells and their contribution to serum autoantibodies during SLE flares have remained uncertain. NIAID-supported researchers used state-of-the-art techniques to create a detailed picture of the interrelationships, diversity, and origins of autoantibody-producing cells from people with SLE during disease flares and compared them to the conventional antibody response that occurs in healthy people after immunization (vaccination). Their analysis indicates that autoantibody-producing B cells in people with SLE arise via several distinct pathways, including pathways that differ from those of a conventional immune response. And, unlike antibody-producing cells that form in response to vaccines, a substantial number of these autoreactive cells persist in the circulation of people with SLE for several months. These findings shed light on the disease process in SLE, help explain the benefit of current therapies that target B cells, and could lead to the design of new therapies.
Reference: Tipton CM et al. Diversity, cellular origin, and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus. Nat Immunol. 2015 Jul;16(7):755-65.
Multiple sclerosis (MS) is a disease of the central nervous system that disproportionately affects women. MS is thought to result from immune cells called auto-reactive T cells that target myelin, the sheath that surrounds and insulates nerve fibers. However, MS patients and healthy people have similar numbers of myelin-reactive T cells. An NIAID-funded study looked for possible functional differences between myelin-reactive T cells from healthy people and those with MS. Researchers compared the production of cytokines (small proteins that regulate the immune system) by these cells and found that the T cells from people with MS produced more inflammation-causing cytokines such as interleukin (IL)-17 compared to healthy people, whereas T cells from healthy people produced more of an anti-inflammatory cytokine called IL-10. The researchers also identified some striking differences between the gene expression profiles of myelin-reactive T cells in people with MS and healthy individuals. These findings suggest that functional differences between myelin-specific T cells from people with MS and healthy individuals play a role in disease development.
Reference: Cao Y et al. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci Transl Med. 2015 May 13;7(287):287ra74.
Anaphylaxis is a severe, potentially life-threatening allergic reaction that may occur in response to food, drugs, or unknown foreign substances. Doctors have reported that anaphylaxis is more common in women than in men, but the reason for this sex-dependent disparity is unclear. In a mouse study designed to explore sex differences in the severity of anaphylaxis, NIAID intramural researchers determined that the increased severity of anaphylactic responses in females may be due to higher levels of estrogen. The researchers found that the higher levels of estradiol (one of the three major estrogens) in female mice increased levels of an enzyme that makes a chemical called nitric oxide (NO) in tissues. Production of NO promotes inflammation by increasing the “leakiness” of blood vessels, enabling inflammation-causing cells and molecules to move more readily through the vessel wall and into adjacent tissues. The researchers showed that blocking NO production completely eliminated the increased severity of the anaphylactic response in female mice. These findings provide novel insight into the sex-dependent disparity in anaphylaxis and highlight the relevance of considering sex as a variable in scientific research. In addition, the findings suggest that drugs that inhibit NO production may be effective for treating certain cases of anaphylaxis.
Reference: Hox V et al. Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production. J Allergy Clin Immunol. 2015 Mar;135(3)729-36.
First-line responses to viruses are initiated by the innate, or inborn, immune system, which then activates the white blood cells of the adaptive immune system. These cells include specific CD8+ T cells that elicit powerful responses targeted to virus-infected cells. After the infection is cleared, most of the virus-specific CD8+ T cells die but some persist in the body as “memory” cells, ready to begin a rapid response to reinfection with a previously encountered pathogen. There are several types of CD8+ memory T cells. Resident memory T cells (Trm cells), rather than circulating in the blood, mostly remain in the tissues where the virus was first encountered, such as the skin or mucous membranes, and enhance protection against reinfection at those sites. However, exactly how Trm cells function in the tissues has remained unclear. NIAID-funded researchers found that activated, virus-specific CD8+ Trm cells in the reproductive tract of female mice can initiate and amplify a nonspecific inflammatory response that provides mucosal protection against unrelated viruses. These findings may help scientists understand previously observed associations between viral infections and exacerbated autoimmune or inflammatory diseases. In addition, the results suggest that scientists could use a vaccine to activate pre-existing Trm cells specific for one pathogen as a strategy to improve local immunity against unrelated pathogens.
Reference: Schenkel JM et al. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science. 2014 Oct 3;346(6205): 98-101.
Imvamune is a smallpox vaccine developed as a safer alternative to existing live virus vaccines. Although immune response to vaccination has been shown to differ by sex for other vaccines, this had not been examined for Imvamune. NIAID-funded researchers conducted a meta-analysis to evaluate sex differences in immune response to this vaccine. The analysis compared patient-level data from three completed randomized clinical trials that tested standard doses of a liquid formulation of Imvamune in healthy participants who had never received a smallpox vaccine. Data from 275 participants (136 men and 139 women) in trials conducted at 13 centers in the United States showed that the short-term antibody response to Imvamune was approximately 27 percent higher in men than in women. The researchers suggest that although the difference is unlikely to modify protection against smallpox, sex should be considered in the further development and deployment of this and other vaccines.
Reference: Troy JD et al. Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE® smallpox vaccine. Vaccine. 2015 Oct 5;33(41):5425-31.
The parasite Plasmodium falciparum is the deadliest and most common malaria species in Africa. Malaria infection during pregnancy has substantial risks for the pregnant woman, her fetus, and the newborn child. The P. falciparum protein VAR2CSA is a promising target for vaccine development against pregnancy-related malaria. NIAID-funded researchers studied fragments of VAR2CSA to determine which part of the protein is targeted in women who have acquired natural immunity after pregnancy and thus identify new targets for a vaccine against pregnancy-associated malaria. In a malaria vaccine trial conducted in Mali, the researchers obtained blood serum samples from 75 children and 77 adults, including 32 men, 29 women who had at least one previous pregnancy, and 16 women who had never been pregnant. The researchers measured the reactivity of the serum to five fragments of VAR2CSA. They found that serum from malaria-exposed women with a history of at least one pregnancy reacted more strongly to two of the five VAR2CSA fragments than serum from men, children, and women who had never been pregnant. In addition, a greater number of pregnancies was associated with stronger reactivity to the two fragments. This finding is consistent with previous observations that with each pregnancy, women exposed to P. falciparum develop more antibodies that protect against the parasite and are associated with better birth outcomes. This study provides insight into how natural immunity to pregnancy-associated malaria is acquired and could inform the development of a vaccine.
Reference: Travassos MA et al. Differential recognition of terminal extracellular Plasmodium falciparum VAR2CSA domains by sera from multigravid, malaria-exposed Malian women. Am J Trop Med Hyg. 2015 Jun;92(6):1190-4.
Clinical studies are critical to develop the knowledge base to ensure the safe and effective use of vaccines and antimicrobials in pregnant women and to enable the prevention and treatment of a range of infectious diseases. Until recently, multiple factors have hindered such studies. A series of NIAID conferences on enrolling pregnant women in clinical trials of antimicrobials and vaccines brought together experts from academia, industry, and governmental and non-governmental agencies to develop a consensus on issues such as inclusion and exclusion criteria, adverse events grading, and markers of health and disease for research studies in pregnant women. This resulted in the publication of an editorial and two guidance papers in September 2013 (1-3). Five additional articles were published in 2015 in a special supplement of Clinical Infectious Diseases funded by the Bill & Melinda Gates Foundation (4). Providing these guidelines to the research community may make it easier for investigators looking to conduct clinical research in pregnant women. Additionally, these guidelines may lead to the standardization of data collection approaches and enhance the value of the data produced by future studies.
Beigi R, Jevaji I, Goldkind S. Research on vaccines and antimicrobials during pregnancy: challenges and opportunities. Vaccine. 2013 Sep 13;31(40):4261-3.
Sheffield J et al. Research on vaccines during pregnancy: reference values for vital signs and laboratory assessments. Vaccine 2013 Sep 13;31(40):4264-73.
Munoz F et al. Research on vaccines during pregnancy: protocol design and assessments of safety. Vaccine 2013 Sep 13;31(40):4274-9.
Nesin M, Frew PM, Read J (eds). Including pregnant women in clinical trials of antimicrobials and vaccines. Clin Infect Dis. 2014 Dec 15;59 (Suppl 7):S395-444.
Science Advances—Fiscal Year 2014
If an HIV-infected individual becomes subsequently infected with a different strain of HIV, they are said to be superinfected. If superinfection occurs, the infected person may progress more rapidly to AIDS and show less sensitivity to therapy. NIAID intramural researchers demonstrated that HIV superinfection occurred at a high rate and was similar to that of primary HIV infection in Ugandan female sex workers. The results of this study differed from a similar study of high-risk female bar workers in Kenya that found the rate of superinfection to be significantly lower than the rate of primary HIV infection. Regardless of the relationship between rates of superinfection and primary infection, however, the findings suggest that individuals who are participating in higher-risk behavior are most likely at increased risk of both primary HIV infection and superinfection. These findings add to the growing evidence that HIV superinfection occurs at a significant rate throughout the world.
Reference: Redd AD et al. Rates of HIV-1 superinfection and primary HIV-1 infection are similar in female sex workers in Uganda. AIDS. 2014 Sep 10;28(14):2147-52.
To achieve an AIDS-free generation, strategies that prevent the transmission of HIV from mother to child after birth are critical, particularly in developing countries. Surprisingly, more than 90 percent of children breastfed from HIV-infected mothers do not contract HIV. NIAID-funded researchers identified a specific protein in breast milk, called Tenascin-C, which neutralizes HIV. Researchers believe that the anti-HIV properties of Tenascin-C contribute to protecting infants against infection. This knowledge about protective proteins in breast milk could be used to develop new safe and effective treatments to prevent postnatal and other types of HIV transmission.
Reference: Fouda GG et al. Tenascin-C is an innate broad-spectrum, HIV-1-neutralizing protein in breast milk. Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18220-5.
Pre-exposure prophylaxis (PrEP) is a Food and Drug Administration-approved HIV prevention approach for people at high risk of contracting HIV. To prevent infection, healthy individuals take daily doses of antiviral therapy. NIAID-funded researchers evaluated the results from a 2010–2012 clinical study in South Africa, which showed that two PrEP strategies in women were ineffective because of lack of patient adherence to daily treatment regimens. The researchers found that social and cultural factors influenced women’s daily use of antiviral therapy. Misunderstandings about the trial were common, including about the rationale for having healthy individuals take antiviral drugs when not infected with HIV. In addition, women were challenged with physical side effects and negative attributes of the treatments and faced social stigmas associated with being on HIV therapy. These results suggest that social and cultural factors must be considered when designing and implementing future HIV PrEP clinical trials.
Reference: van der Straten A et al. Women's experiences with oral and vaginal pre-exposure prophylaxis: the VOICE-C qualitative study in Johannesburg, South Africa. PLoS One. 2014 Feb 21;9(2):e89118.
Asthma is a severe and chronic disease that causes wheezing, breathlessness, chest tightness, and coughing. Development of asthma is influenced by both genetic and environmental factors. The prevalence of asthma in girls increases after puberty, and previous studies have identified an association between asthma and sex hormones—both those produced by the body and those in medications. In this study, NIAID-supported researchers identified a process by which sex hormones lead to modifications of the gene GATA3, which in turn regulate the so-called T-helper 2 (Th2) immune response associated with asthma. This process was influenced by both oral contraceptive use and a woman’s age at first menstrual cycle, revealing a pathway that may explain how sex hormones in women can increase asthma prevalence after puberty.
To determine the genetic factors and processes that influence asthma incidence in adolescent females, this team of investigators analyzed how the process of DNA methylation of genes in the Th2 pathway affects asthma risk in girls 10 to 18 years of age. DNA methylation is a type of chemical modification that alters gene activity while leaving the underlying genetic code unchanged. The results show that interaction between DNA methylation and genetic sequence variations in genes of the Th2 pathway likely contributes to asthma risk in girls. Furthermore, this effect may vary with age, which may influence asthma during the transition from childhood to adulthood.
References: Guthikonda K et al. Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation. Clin Epigenetics. 2014 Sep 19;6(1):17.
Zhang H et al. The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition. Clin Epigenetics. 2014 Apr 15;6(1):8.
References: Guthikonda K et al. Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation. Clin Epigenetics. 2014 Sep 19;6(1):17.
Zhang H et al. The interplay of DNA methylation over time with Th2 pathway genetic variants on asthma risk and temporal asthma transition. Clin Epigenetics. 2014 Apr 15;6(1):8.
Whereas genes on the human sex chromosomes are known to contribute to differences in disease prevalence and risk, the effect of genes from autosomal (non-sex) chromosomes on these differences has not been as well studied. NIAID-funded researchers searched for sex-specific asthma risk genes through a genome-wide scan for interactions between autosomal genes and male or female physiological factors. The researchers studied a group of ethnically diverse individuals of European American, African American, African Caribbean, and Latino ancestries. The study identified six sex-specific chromosome regions, or loci, associated with asthma risk, all of which were connected with specific ancestries. One chromosome region, the interferon regulatory factor 1 (IRF1) locus, contains a gene that has a known role in immune pathways involved in asthma. These findings, along with prior reports of sex-specific differences in interferon responses, suggest that the IRF1 locus is a strong candidate for contributing to male-specific asthma risk.
Reference: Myers RA et al. Genome-wide interaction studies reveal sex-specific asthma risk alleles. Hum Mol Genet. 2014 Oct 1;23(19):5251-9.
In the United States, food allergy and asthma occur in approximately 5 percent and 8.4 percent of people, respectively. Researchers have long suspected that maternal diet during pregnancy plays a role in the development of childhood allergy and asthma but previous study results have been conflicting. Unlike previous analyses that focused on late pregnancy, this NIAID-supported study examined the effect of maternal diet during the first two trimesters of pregnancy on the development of childhood asthma and allergy. The results showed that higher maternal intake of peanut, milk, and wheat during early pregnancy was associated with reduced odds of mid-childhood allergy and asthma, suggesting that eating these foods during pregnancy could help curb the rising incidence of asthma and allergy in the United States.
Reference: Bunyavanich S et al. Peanut, milk, and wheat intake during pregnancy is associated with reduced allergy and asthma in children. J Allergy Clin Immunol. 2014 May;133(5):1373-82.
Long-term immunity to infectious diseases relies on the immune system’s ability to recognize previously encountered pathogens during reinfections. This immunological memory is facilitated in part by specific components of the immune system called memory T cells. Generated during a prior infection, these cells are ever ready to mount a rapid and powerful response to reinfections. Originally thought to reside only in circulatory systems such as blood, recent studies identified resident memory T cells (Trm) that remain in specific tissues where the infection was first encountered. In this NIAID-funded study, vaginal infection of mice with herpes simplex virus (HSV) led to the generation of local Trm that provided better protection against HSV than did circulatory memory T cells. These results suggest that alternative vaccine strategies for STIs may result in improved disease prevention in women.
Reference: Iijima N, Iwasaki A. T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells. Science. 2014 Oct 3;346(6205):93-8.
Systemic lupus erythematosus (SLE), more commonly known as lupus, is an autoimmune disease. Inflammation caused by lupus can affect many body systems, including the central nervous system, joints, skin, kidneys, blood cells, heart, and lungs. Approximately 322,000 Americans are diagnosed with or suspected of having SLE, and 90 percent of people with lupus are women. People with SLE produce abnormal antibodies (autoantibodies) that target DNA and RNA from the body’s own cells, contributing to inflammation. Autoantibody production is controlled in part via signals transmitted by two different receptor molecules, TLR7 and TLR9, which are found in various types of immune cells. Through genetic manipulation in mouse models of lupus, NIAID-funded investigators found that TLR7- and TLR9-mediated signaling in immune cells called B cells have opposing effects on inflammation and on the types of autoantibodies produced. These findings stress the critical importance of dysregulated TLR signaling in B cells in the development of SLE and could inform efforts to target TLR signals therapeutically in SLE and other disorders characterized by autoantibody production.
Reference: Jackson SW et al. Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. J Immunol. 2014 May 15;192(10):4525-32. 2014.
Crohn’s disease is a form of inflammatory bowel disease that affects women with increased severity and at a higher rate than men. To investigate possible mechanisms for this disparity, NIAID-funded researchers studied a strain of mice known as SAMP mice that spontaneously develop chronic intestinal inflammation resembling human Crohn’s disease, with a similar disparity between females and males. They found that T regulatory (Treg) cells, which are known to modulate immune responses, were reduced in frequency and activity in female mice compared to male mice. Male SAMP mice treated with estrogen responded by increasing Tregs that reduced Crohn’s-like symptoms, whereas females were resistant to the effect of estrogen. Further studies showed that estrogen signaling at the receptor level in female mice is disrupted and leads to fewer protective Treg cells. These findings suggest that therapies designed to enhance protective estrogen-mediated signaling in Tregs may be beneficial for treating chronic inflammatory disorders such as Crohn’s disease.
Reference: Goodman WA et al. Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn's-like ileitis. Mucosal Immunol. 2014 Sep;7(5):1255-65.
Pregnancy-associated malaria (PAM), or placental malaria, is associated with low birth weight, maternal anemia, and gestational hypertension and is a major cause of death and disease for women and their children in sub-Saharan Africa. NIAID intramural investigators recently shed light on acquired immunity to PAM in mothers and their unborn children and infants. Clinical immunity to PAM is attributed to antibodies that recognize the malaria parasite Plasmodium falciparum protein VAR2CSA on the infected red blood cell surface. However, there has been no consensus on which of VAR2CSA’s six Duffy binding-like (DBL) domains would be most effective in eliciting immunity if used in a vaccine. NIAID-funded investigators have provided the first evidence that, in P. falciparum-exposed women who have had multiple pregnancies, the DBL2χ, DBL3χ, and DBL5ε domains are targeted by antibody opsonization. This finding is highly significant, as antibody opsonization is the process by which a pathogen is marked for ingestion and destruction by white blood cells called phagocytes. This discovery reveals key information for developing effective preventive and therapeutic approaches for PAM and potentially other infectious diseases.
Reference: Lambert LH et al. Antigen reversal identifies targets of opsonizing IgGs against pregnancy-associated malaria. Infect Immun. 2014 Nov;82(11):4842-53.
Pregnant women are unusually vulnerable to infection with the foodborne bacterium Listeria monocytogenes (Lm), with often deadly consequences for the developing fetus. Vaccinating women before conception has been shown to protect pregnant women and their babies from a wide range of infections. This NIAID-funded study examined whether vaccination for Lm before conception protected against subsequent infection by virulent Lm in pregnant mice. The results showed that even though the mice generated protective Lm-specific immune cells, susceptibility to Lm during pregnancy could not be overcome when researchers mated mice of two different genetic strains. By contrast, vaccination was effective when the parent mice (and thus the mother and fetus) were of the same strain. These findings show that maternal-fetal genetic differences dictate the ineffectiveness of pre-conception vaccination against fetal complications and provide new clues on how physiological shifts during pregnancy regulate immune responsiveness.
Reference: Clark DR et al. Perinatal Listeria monocytogenes susceptibility despite preconceptual priming and maintenance of pathogen-specific CD8(+) T cells during pregnancy. Cell Mol Immunol. 2014 Nov;11(6):595-605.
Females often have more robust immune responses than males to infections and vaccination for reasons that scientists do not fully understand. NIAID-funded researchers showed that, after seasonal influenza vaccination, women produced more antibodies that could effectively neutralize the virus compared to men. Gene expression studies showed that men with weak vaccine responses had high expression levels in a cluster of lipid metabolism genes that may be controlled by the male hormone testosterone. Men with high testosterone levels and elevated gene expression of this cluster exhibited a lower immune response to influenza vaccination compared to women or to men with low testosterone. The results suggest that male hormones may suppress immune responses to vaccines by altering expression of specific genes.
Reference: Furman D et al. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):869-74.
Mycoplasma genitalium is a sexually transmitted disease associated with inflammation of the reproductive system. Among women, the worldwide prevalence of M. genitalium infection is approximately 1 to 5 percent. For men, previous studies have shown that circumcision reduced the risk of acquiring M. genitalium. To determine whether circumcision would also protect female partners of circumcised men, NIAID-funded researchers conducted a clinical trial in Uganda and found that male circumcision did not protect female partners from M. genitalium infection. The researchers suggested that multiple factors may have contributed to the study results. For example, female partners may have engaged in outside relationships, or circumcision may not have affected the infected genital areas of men, such as the urethra.
Reference: Tobian AAR et al. Male circumcision and Mycoplasma genitalium infection in female partners: a randomised trial in Rakai, Uganda. Sex Transm Infect. 2014 Mar;90(2):150-4.
Science Advances—Fiscal Year 2013
Intermittent treatment with a drug combination called sulfadoxine-pyrimethamine has been used to prevent many harmful consequences of malaria infection during pregnancy. However, it fails to prevent placental malaria, a common complication of malaria in pregnancy, in areas of the world where resistance to these drugs is widespread. A longitudinal study in Tanzania led by NIAID researchers demonstrated for the first time that this treatment strategy was associated with a higher risk of malaria infection and severe malarial disease in children born to women who had placental malaria. The findings could have important implications for malaria control efforts worldwide.
Reference: Harrington WE et al. Intermittent preventive treatment in pregnant women is associated with increased risk of severe malaria in their offspring. PLoS One. 2013;8(2):e56183.
This NIAID-funded study used a mouse model to develop a novel vaccination strategy against herpes simplex virus 2 that relies on T-cell activation rather than neutralizing antibody production. Known as “prime and pull,” the first step is a conventional vaccination to activate T cells throughout the body (prime). This is followed by the application of a small molecule to the genital area, which draws in the activated T cells (pull). These cells establish a niche in the tissue and are ready to provide protection against future infection.
Reference: Shin H, Iwasaki A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature. 2012 Nov 15; 491(7424):463-7.
A team led by researchers from NIAID and their colleagues examined the frequency of cervical human papillomavirus (HPV) detection among HIV-infected women in a resource-limited setting in Uganda. The women were followed monthly for six months before and after initiation of antiretroviral therapy (ART). The researchers did not observe an effect of ART on monthly HPV detection, even if the women’s immune systems became healthier or HIV replication was suppressed. They found that only older age and higher pre-ART numbers of CD4+ immune cells, which are targeted by HIV, were associated with a significantly lower risk of detecting HPV. The results highlight the importance of continued and consistent screening for HPV, even after starting ART.
Reference: Rositch AF et al. Frequent detection of HPV before and after initiation of antiretroviral therapy among HIV/HSV-2 co-infected women in Uganda. PLoS One. 2013;8(1):e55383.
Herpes simplex virus type 2 (HSV-2) is a common sexually transmitted infection and a major cause of genital ulcers worldwide. To understand the relationship between starting HIV treatment and developing genital ulcers and/or reactivating an inactive herpes infection, NIAID researchers and their colleagues studied two groups of women from Rakai, Uganda, who were co-infected with HIV and HSV-2. After the initiation of antiretroviral drug treatment for HIV, the prevalence of both genital ulcer disease (GUD) and reactivation of herpes infection increased significantly among study participants. The researchers suggest that this may have been due to an inflammatory syndrome that occurs when the immune system overreacts to a microbe following antiretroviral treatment. Treatment with the antiviral drug acyclovir reduced GUD and evidence of herpes virus reactivation in the study patients, suggesting that it should be considered as a way to mitigate these effects following the start of antiretroviral therapy in HIV-infected individuals.
Reference: Tobian AA et al. Reactivation of herpes simplex virus type 2 after initiation of antiretroviral therapy. J Infect Dis. 2013 Sep 1;208(5):839-46.
The prevalence in the general population of a bacterial lung infection known as pulmonary nontuberculous mycobacterial (PNTM) disease has risen in recent decades, especially in older women, despite their lack of any apparent immunological problems. Individuals can be predisposed to PNTM, however, if they have conditions that lead to lung damage or to impaired self-clearing mechanisms of the human respiratory tract. Guided by this knowledge, NIAID investigators compared the functioning of the epithelial cells that line and clear airways in PNTM patients and in healthy subjects. They found defective epithelial cell function in PNTM patients but not in healthy individuals. In tissue samples from PNTM patients, the researchers could selectively return these defects to normal using therapeutics approved for unrelated conditions (e.g., impotence). The results suggest that targeting the underlying mechanisms that make people susceptible to PNTM may serve as a therapeutic approach to this disease that can readily be evaluated clinically.
Reference: Fowler CJ et al. Abnormal nasal nitric oxide production, ciliary beat frequency, and Toll-like receptor response in pulmonary nontuberculous mycobacterial disease epithelium. Am J Respir Crit Care Med. 2013 Jun 15;187(12):1374-81.
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The human vaginal mucosa is a major entry site for sexually transmitted pathogens, but the immunological responses within the vagina are poorly understood. NIAID-supported researchers demonstrated that the earliest immune responses in the vagina can be orchestrated by the activation of four different immune cell types. Each cell type then directs the production of different T cells that provide protective immune responses. The results of this study provide insights that will lead to the design and development of effective mucosal vaccines against many sexually transmitted diseases.
Reference: Duluc D, Gannevat J, Anguiano E. Functional diversity of human vaginal APC subsets in directing T-cell responses. Mucosal Immunol. 2013 May;6(3):626-38.
Regulatory T cells (Tregs) actively suppress activation of the immune system and prevent inflammation. A subset of Tregs, known as induced T-regulatory (iTreg) cells, are difficult to study because they are unstable. Using animal models, NIAID-funded investigators found that progesterone, a female hormone, can generate highly stable iTreg cells that are efficient in suppressing tissue inflammation. These results show great therapeutic promise for autoimmune diseases such as multiple sclerosis and inflammatory bowel disease.
Reference: Lee JH et al. Progesterone suppresses the mTOR pathway and promotes generation of induced regulatory T cells with increased stability. Eur J Immunol. 2012 Oct;42(10):2683-96.
Researchers funded by NIAID created a new statistical model that allowed further analysis of data from an early-phase safety study of the vaginally formulated UC781 gel as a rectal microbicide to prevent HIV acquisition. This new statistical method allowed researchers to determine specific relationships between tissue drug concentrations and the effectiveness of UC781 in a biopsy challenge model, which tests the ability of HIV to infect small samples (biopsies) of rectal tissue from patients. This work provided the first estimate of the concentration of drug in gel that might be required to prevent HIV transmission and identified the biopsy challenge model as a potential bridge to link drug concentration in tissues with possible efficacy of the drug.
Reference: Richardson-Harman N et al. Dose-response relationship between tissue concentrations of UC781 and explant infectibility with HIV type 1 in the RMP-01 rectal safety study. AIDS Res Hum Retroviruses. 2012 Nov;28(11):1422-33.
Reliable and cost-effective methods to estimate HIV incidence help monitor the epidemic, identify at-risk populations, and evaluate prevention strategies. NIAID-supported scientists compared three methods for estimating the HIV incidence rate in more than 2,000 women enrolled in the HIV Prevention Trials Network 064 study. They found that the annual HIV incidence estimate based on acute infection at enrollment was tenfold higher than the incidence estimate based on the time when participants developed an immune response to HIV or on a new method that uses an algorithm that combines the results of several lab tests. This preliminary evidence suggests that the new approach could be useful in estimating HIV incidence.
Reference: Eshleman SH et al. Use of a multifaceted approach to analyze HIV incidence in a cohort study of women in the United States: HIV Prevention Trials Network 064 Study. J Infect Dis. 2013 Jan 15;207(2):223-31.
An NIAID-funded study evaluated HIV incidence and described behaviors for up to 12 months among U.S. women living in communities with high HIV prevalence and high poverty rates. Among 2,099 high-risk women aged 18 to 44 years (85.9 percent black and 11.7 percent of Hispanic ethnicity), 32 were diagnosed with HIV infection at the time of enrollment. The annual incidence of HIV was 0.32 percent. Older age, substance use, and having an HIV-infected partner were associated with high HIV prevalence. This study enrolled a cohort of women with a substantially higher HIV incidence rate than the national estimate in the general population of U.S. black women.
Reference: Hodder SL et al. HIV acquisition among women from selected areas of the United States: a cohort study. Ann Intern Med. 2013 Jan 1;158(1):10-8.
If an HIV-positive person becomes subsequently infected with a different strain of HIV, they are said to be “superinfected.” If superinfection occurs, the infected person may experience a more rapid progression to AIDS and show less sensitivity to therapy. NIAID-funded investigators studied samples from a cohort (selected group) of more than 100 high-risk women in Mombasa, Kenya, to determine if the incidence of superinfection was different from that of initial infection. Laboratory analysis detected 21 cases of superinfection in the cohort, which translated to an incidence rate of 2.61 per 100 person years. By comparison, the incidence rate for initial infection was 5.75 per 100 person years. Furthermore, the immune responses to the initial infection appeared to provide some protection against superinfection. This is the first rigorous study to report that HIV infection reduces the risk of reinfection, raising the possibility that immune responses to natural infection are partially protective. Because the superinfection risk changes with time, the researchers suggest that a window of protection may coincide with the maturing of HIV-specific immunity.
Reference: Ronen K et al. HIV-1 superinfection occurs less frequently than initial infection in a cohort of high-risk Kenyan women. PLoS Pathog. 2013 Aug;9(8):e1003593.
Few studies exist of the life expectancy of HIV-infected individuals receiving antiretroviral therapy (ART) in low- and middle-income countries. To address this issue, NIAID-supported investigators used data from South African populations undergoing ART for the first time. They found that the average life expectancy of HIV-infected South African women starting therapy between the ages of 20 and 60 was significantly higher than that of the corresponding group of HIV-infected men. The most significant factor determining the life expectancy of treated patients was their age at ART initiation, with longer life expectancies for those who started treatment at a younger age.
A hypothetical 20-year-old, HIV-infected woman’s life expectancy was approximately 43 years if her CD4 T-cell count was above 200 cells per microliter when starting treatment. (The definition of AIDS includes having a CD4 count below 200.) By contrast, women starting therapy with a CD4 count below the AIDS-defining level lived for only 29.5 years on average. Moreover, the life expectancies of HIV-infected individuals with CD4 counts at or above the AIDS-defining level were between 70 and 86 percent of those of uninfected adults of the same age and sex. Life expectancies were 15 to 20 percent higher in people who survived their first two years after beginning therapy than in patients of the same age who had just started therapy. This study suggests that HIV-infected individuals in South Africa could have near-normal lifespans, provided that they start ART before their CD4 count drops below 200.
Reference: Johnson LF et al. Life expectancies of South African adults starting antiretroviral treatment: collaborative analysis of cohort studies. PLoS Med. 2013;10(4):e1001418.
Researchers estimated the proportions, timing, and predictors of AIDS-related and non-AIDS-related mortality among HIV-infected and uninfected individuals enrolled in two long-standing NIAID-supported cohort studies. They analyzed data from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) from 1984 to 2008 and 1996 to 2008, respectively, and compared information before and after the era when highly active antiretroviral therapy was available. Once this therapy became readily available, the proportion of deaths from non-AIDS causes increased from 6 percent to 53 percent among HIV-positive MACS participants, and the median age of people who died from non-AIDS-related causes after 35 years of age increased from 49 to 66 years. In addition, in both study groups, the median ages at time of non-AIDS-related death were lower for HIV-positive individuals than for uninfected individuals. These results show that after more effective therapy became available, patients were less likely to die from an AIDS-related condition than from a non-AIDS-related condition.
Reference: Wada N et al. Cause-specific life expectancies after 35 years of age for human immunodeficiency syndrome-infected and human immunodeficiency syndrome-negative individuals followed simultaneously in long-term cohort studies, 1984-2008. Am J Epidemiol. 2013 Jan 15;177(2):116-25.
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Last Updated February 16, 2016