Background: Plasma HIV RNA is the most significant determinant of cervical HIV shedding. However, shedding is also associated with sexually transmitted infections (STIs) and cervical inflammation. The mechanism by which this occurs is poorly understood. There is evidence that systemic immune activation promotes viral entry, replication, and HIV disease progression. We hypothesized that systemic immune activation would be associated with an increase in HIV genital shedding.
Methods: Clinical assessments, HIV RNA in plasma and genital secretions, and markers of immune activation (CD38+DR+ and CD38−DR−) on CD4+ and CD8+ T cells in blood were evaluated in 226 HIV+ women enrolled in the Women's Interagency HIV Study. There were 569 genital evaluations of which 159 (28%) exhibited HIV RNA shedding, defined as HIV viral load >80 copies per milliliter. We tested associations between immune activation and shedding using generalized estimating equations with logit link function.
Results: In the univariate model, higher levels of CD4+ and CD8+ T-cell activation in blood were significantly associated with genital tract shedding. However, in the multivariate model adjusting for plasma HIV RNA, STIs, and genital tract infections, only higher levels of resting CD8+ T cells (CD38−DR−) were significantly inversely associated with HIV shedding in the genital tract (odds ratios = 0.44, 95% confidence interval: 0.21 to 0.9, P = 0.02).
Conclusions: The association of systemic immune activation with genital HIV shedding is multifactorial. Systemic T-cell activation is associated with genital tract shedding in univariate analysis but not when adjusting for plasma HIV RNA, STIs, and genital tract infections. In addition, women with high percentage of resting T cells are less likely to have HIV shedding compared with those with lower percentages. These findings suggest that a higher percentage of resting cells, as a result of maximal viral suppression with treatment, may decrease local genital activation, HIV shedding, and transmission.
*Maternal, Child and Adolescent Center for Infectious Diseases and Virology, Department of Pediatrics, Division of Infectious Disease, University of Southern California Keck School of Medicine, Los Angeles, CA;
†Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA;
‡Department of Medicine, Division of Infectious Diseases, Georgetown School of Medicine, Washington, DC;
§Departments of Medicine and Epidemiology and Population Health, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx NY;
‖Department of Obstetrics and Gynecology, Maimonides Medical Center and SUNY Downstate, Brooklyn, NY;
¶Departments of Medicine, Rush University and Cook County Bureau of Health, Chicago, IL;
#Department of Clinical Pharmacology, University of California San Francisco School of Pharmacy, San Francisco, CA;
**Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL.
Correspondence to: LaShonda Y. Spencer, MD, Maternal, Child and Adolescent Center for Infectious Diseases and Virology, Department of Pediatrics, Division of Infectious Disease, University of Southern California Keck School of Medicine. 1000 S Fremont Avenue, Unit 62, A10, Suite 10220, Alhambra, CA 91803 (e-mail: email@example.com).
Supported by grant RO1 AI052065 (K.A.) (R01 and R56) from the National Institute of Allergy and Infectious Diseases and grant R01 CA85178 (H.D.S.) from National Cancer Institute. The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases, with additional co‐funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Mental Health. Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Deafness and other Communication Disorders, and the NIH Office of Research on Women's Health. WIHS data collection is also supported by UL1‐TR000004 (UCSF CTSA) and UL1‐TR000454 (Atlanta CTSA).
Presented at: Conference on Retroviruses and Opportunistic Infections 2008, Boston, MA (Poster 674, abstract T-136).
The authors have no conflicts of interest to disclose.
Received December 16, 2014
Accepted July 08, 2015