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Science Advances – Fiscal Year 2013

NIAID conducts and supports research to prevent, diagnose, and treat infectious and immunological diseases that affect the health of women and girls.

Parasitic Infectious Diseases
Human Immunology

Parasitic Infectious Diseases

Preventive Treatment Strategy in Pregnant Women Is Associated With Higher Malaria Risk for Their Children

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.

Infectious Diseases (Other Than HIV/AIDS)

Experimental Vaccine Strategy Shows Promise Against Genital Herpes

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.

Frequent Detection of Human Papillomavirus in HIV-Infected Women in Uganda

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.

Development of Genital Ulcers and Reactivation of Herpes Simplex Virus in HIV-Infected Women After Starting Antiretroviral Therapy

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.

Insights on the Increased Prevalence of Pulmonary Nontuberculous Mycobacterial Infections in Older Women

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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Human Immunology

Insights on the Human Vaginal Immune Response in Health and Disease

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.

Progesterone Promotes the Stability of Immune Cells With Therapeutic Potential

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.

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Statistical Method Shows Relationships Between Tissue Drug Concentrations and Effectiveness of an Anti-HIV Microbicide

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.

Multifaceted Approach Could Help Estimate HIV Incidence

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.

Risk Factors for HIV Acquisition Among Women From Selected Areas of the United States

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.

HIV Superinfection Is Less Frequent Than Initial Infection in a Cohort of High-Risk Kenyan Women

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.

HIV-Infected South African Adults Who Start Antiretroviral Therapy Early Have Near-Normal Life Expectancies

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.

Life Expectancies of HIV-Infected Individuals in Established NIAID Cohort Studies

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.

See earlier research overviews.

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Last Updated May 06, 2014

Last Reviewed May 06, 2014