HIV-Specific CD8+ Lymphocytes in Semen Are Not Associated with Reduced HIV Shedding

Abstract

Sexual contact with HIV-infected semen is a major driving force behind the global HIV pandemic. Little is known regarding the immune correlates of virus shedding in this compartment, although HIV-1-specific CD8+ T cells are present in semen. We collected blood and semen from 27 chronically HIV-infected, therapy-naive men without common sexually transmitted infections or urethral inflammation and measured HIV-1 RNA viral load and cytokine/chemokine levels in both compartments. HIV-1 RNA levels were 10-fold higher in blood than semen, but discordantly high semen shedding was associated with higher semen levels of the proinflammatory cytokines IL-6, IL-8, IL-12, and IFN-γ. Virus-specific CD8+ T cell epitopes were mapped in blood by IFN-γ ELISPOT, using an overlapping HIV-1 clade B peptide matrix, and blood and semen CD8+ T cell responses were then assayed ex vivo using intracellular IFN-γ staining. HIV-specific CD8+ responses were detected in 70% of semen samples, and their frequency was similar to or higher than blood. There was no correlation between the presence of virus-specific CD8+ T cells in semen and levels of HIV-1 RNA shedding. Among participants with detectable CD8+ IFN-γ semen responses, their relative frequency was not associated with reduced HIV-1 RNA shedding, and their absolute number was correlated with higher levels of HIV-1 RNA semen shedding (r = 0.6; p = 0.03) and of several proinflammatory cytokines. Neither the presence nor the frequency of semen HIV-specific CD8+ T cell IFN-γ responses in semen correlated with reduced levels of HIV RNA in semen.

Impact of Mucosal Inflammation on Cervical Human Immunodeficiency Virus (HIV-1)-Specific CD8 T-Cell Responses in the Female Genital Tract during Chronic HIV Infection

“…Although positive correlations between plasma viral loads and genital shedding have been detected previously (2,26,27,36), this association is still somewhat controversial, with some studies failing to find any significant correlation between HIV viral loads in the blood and at the genital mucosa (34,36). Local factors in the genital tract may influence viral replication.…”

“…Cellular and humoral immune responses against HIV have been detected at the cervix and in semen of both HIV exposed and uninfected (highly exposed but persistently seronegative [HEPS]) and HIV-infected individuals (14,15,18,34). It has therefore been suggested that such responses may be important correlates of protection against HIV locally.…”

Associations between Virologic and Immunologic Dynamics in Blood and in the Male Genital Tract

“…It is, therefore, possible that an accumulation of infected CD4 ϩ T cells in semen together with enhanced cellular HIV transcription and replication in activated T lymphocytes (6,17,26,32,65,67,83) could increase the risk of sexual transmission of HIV. Moreover, persistent immune activation of lymphocytes in semen and in blood may impact HIV disease progression and overall clinical outcome.…”

Seminal Plasma HIV-1 RNA Concentration Is Strongly Associated with Altered Levels of Seminal Plasma Interferon-γ, Interleukin-17, and Interleukin-5

“…17,21 Median levels of blood and seminal plasma cytokines were compared between men with and without atypically high ratios of seminal versus blood plasma HIV-1 RNA levels using the Wilcoxon test. Finally, a separate subanalysis was performed to compare seminal:blood plasma cytokine ratios in men with detectable seminal plasma HIV-1 RNA levels (defined as > 100 copies/ml) and those with undetectable levels ( £ 100 copies/ml), also using the Wilcoxon test.…”

“…Berlier et al described a positive correlation with interleukin (IL)-1b, 15 while Storey et al described a positive correlation with RANTES, 16 and Sheth et al showed positive correlations with IL-6, IL-8, IL-12, and interferon (IFN)-c. 17 Furthermore, Lisco et al recently suggested that HIV-1 infection causes a ''reprogrammed cytokine network'' in the seminal plasma with elevated levels of several proinflammatory cytokines including IL-1a, IL-1b, IL-6, and IL-8, which do not correlate with blood plasma cytokine levels. 18 This suggests that cytokine expression is compartmentalized and that seminal plasma cytokines are likely produced within the male genital tract.…”