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Women's Health Science Advances—Fiscal Year 2015

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/AIDS
Immunology
Infectious Diseases (Other Than HIV/AIDS)

HIV/AIDS

Exploring Racial/Ethnic Differences in Liver-Related Mortality in HIV/HCV-Co-infected Women

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.

Postpartum HIV Superinfection Is Not Associated With Mother-to-Child Transmission Through Breastfeeding

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.

Untreated HIV Infection Has No Association With Low Bone Mineral Density

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.

Concurrent Use of Long-Acting Contraceptive and Antiretroviral Therapy Is Safe

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.

Sex Differences in Response to the First-Line HIV Drug Atazanavir

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.

Pre-Exposure Prophylaxis Fails to Prevent HIV Transmission in Study of African Women

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.

HIV Infection Has a Small but Negative Effect on Cognitive Function in Women

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.

Immunology

A Possible Mechanism for Sex Differences in Severe Asthma

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.

New Insights Into Disease Flares in Systemic Lupus Erythematosus

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.

Functional Differences in Immune Cells Provide Clues to Disease Process in Multiple Sclerosis

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.

Estrogen Increases the Severity of Severe Allergic Reactions

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.

Immune Cells Amplify Antiviral State in Tissues

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.

Infectious Diseases (Other than HIV/AIDS)

Sex Differences in Immune Response to Smallpox Vaccine

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.

New Vaccine Targets for Pregnancy-Associated Malaria

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.

Including Pregnant Women in Clinical Trials of Antimicrobials and Vaccines

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.

References

  1. Beigi R, Jevaji I, Goldkind S. Research on vaccines and antimicrobials during pregnancy: challenges and opportunities. Vaccine. 2013 Sep 13;31(40):4261-3.
  2. 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.
  3. Munoz F et al. Research on vaccines during pregnancy: protocol design and assessments of safety. Vaccine 2013 Sep 13;31(40):4274-9.
  4. 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.
 

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Last Updated February 16, 2016