Persistence of Genital Tract T Cell Responses in HIV-Infected Women on Highly Active Antiretroviral Therapy

Abstract

Initiation of highly active antiretroviral therapy (HAART) for HIV-infected individuals is associated with control of viremia, improved CD4 counts, and declining systemic HIV-specific immune responses. While HAART effectively reduces plasma viremia, it remains unclear how effectively antiretroviral drugs reach mucosal surfaces, such as those of the genital tract. The aim of this study was to determine the effect of HAART on genital tract CD4 T cell reconstitution, HIV shedding, and HIV-specific T cell responses. Cervical cytobrush and blood specimens were obtained from 35 HIV-infected, HAART-naïve women and 27 women on HAART in order to investigate HIV Gag-specific T cell responses by intracellular gamma interferon (IFN-␥) staining. Interleukin 1␤ (IL-1␤), IL-6, and IL-8 concentrations were measured by enzyme-linked immunosorbent assays (ELISA). We show that for HIV-infected women, HAART is associated with significantly improved CD4 T cell counts both in blood and at the cervix. While HAART effectively suppressed both blood and cervical viremia, HIV-specific CD8 T cell responses in blood were lost, while those at the cervix were preserved.

Immune Responses to HIV in the Female Reproductive Tract, Immunologic Parallels with the Gastrointestinal Tract, and Research Implications

“…In a recent cross-sectional study of 62 HIV-positive women, including 35 on HAART, Mkhize and colleagues demonstrated that HAART is associated with higher CD4+ T-cell percentages at the cervical mucosa33. Genital tract HIV shedding was significantly associated with the amount of HIV RNA circulating in blood, and was fully suppressed in HAART-compliant women.…”

“…28 Recently, progress has been made in utilizing minimally invasive clinical specimens, notably cervical cytobrushes and CVL for immunological assays. [29][30][31][32][33][34][35][36] Gumbi et al 32 studied the relationship between mucosal inflammation and HIV-specific CD8 + T-cell responses in the cervix. They found that increased levels of proinflammatory cytokines (i.e., TNF-a, IL-1b, IL-6, and IL-8) in CVL fluid were significantly associated with HIV shedding in the genital tract.…”

ART influences HIV persistence in the female reproductive tract and cervicovaginal secretions

“…These results demonstrate that the reduction in the percentages of CD4 + T cells observed in CVS of order to understand the cellular dynamics that occur in the FRT after local versus distal HIV infection, we evaluated all 3 modes of mucosal HIV acquisition following exposure to cell-free and/or cell-associated HIV (Supplemental Table 1). Specifically, to complement the data presented above obtained after vaginal exposure, we analyzed the levels of human CD4 + T cells in PB, FRT, and CVS following rectal and oral HIV exposures ( Figure 4 + T cells than infected women not receiving treatment (57). In addition -as indicated above -prior to treatment, there was a dramatic increase in total CD8 + T cells in CVS ( Figure 6C).…”

Effect of HIV Infection and Menopause Status on Raltegravir Pharmacokinetics in the Blood and Genital Tract

“…In our study, 2 of 5 postmenopausal women were provided a full course of treatment for bacterial vaginosis but not rescreened prior to enrollment. Additionally, genital HIV RNA positively correlates with IL-6 and IL-1β in the female genital tract[28] and has been observed in women on antiretroviral therapy despite undetectable plasma HIV RNA [5]. Thus, the trend towards increased raltegravir exposure in HIV-infected women vs negative women may be due to attenuated p-glycoprotein efflux transporter expression secondary to inflammation in the genital tract.…”