NIAID conducts and supports research to prevent, diagnose, and treat infectious and immunological diseases that affect the health of women and girls.
HIV/AIDSImmunologyInfectious Diseases (Other Than HIV/AIDS)
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, Jaeger FH, Amos JD 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, Stadler J, Montgomery E 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.
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, Garg RR, Reuter BK 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.
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, Hejblum BP, Simon N 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, Gaydos C, Gray RH 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, Morrison R, Fried M 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 and 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, Gravatt PE, Tobian AA 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, Grabowski MK, Serwadda D 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, Olivier KN, Leung JM 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, Lydon JP, Kim CH 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, Mauck C, McGowan I 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, Hughes JP, Laeyendecker O 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, Justman J, Hughes JP 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, McCoy CO, Matsen FA 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, Mossong J, Dorrington RE 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, Jacobson LP, Cohen M 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 January 13, 2015