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Background: HIV preferentially establishes productive infection in activated CD4+ T cells. Since proportions of activated CD4+ T cells vary between individuals, this study aimed to determine if individuals with a greater proportion of activated CD4+ T cells would be more susceptible to in vitro HIV infection., Methodology/principal Findings: Unstimulated peripheral blood mononuclear cells (PBMC) from various donors were inoculated with HIV(ML1956)in vitro. HIV replication was evaluated by HIV p24 ELISA of culture supernatants and intracellular staining for HIV p24, which was detected by flow cytometry. Baseline T cell phenotypes and infected cell phenotypes were also evaluated by flow cytometry. Ex vivo phenotyping at the time of blood draw showed that elevated T cell activation and reduced Tregs were associated with increased cellular susceptibility to in vitro infection. Furthermore, the infected CD4+ T cell population was enriched for activated cells., Conclusion/significance: These data suggest that CD4+ T cell quiescence provides an environment less conducive to the establishment of HIV infection by limiting the pool of activated target cells.

Background: Design of effective vaccines against the human immunodeficiency virus (HIV-1) continues to present formidable challenges. However, individuals who are exposed HIV-1 but do not get infected may reveal correlates of protection that may inform on effective vaccine design. A preliminary gene expression analysis of HIV resistant female sex workers (HIV-R) suggested a high expression CD26/DPPIV gene. Previous studies have indicated an anti-HIV effect of high CD26/DPPIV expressing cells in vitro. Similarly, high CD26/DPPIV protein levels in vivo have been shown to be a risk factor for type 2 diabetes. We carried out a study to confirm if the high CD26/DPPIV gene expression among the HIV-R were concordant with high blood protein levels and its correlation with clinical type 2 diabetes and other perturbations in the insulin signaling pathway., Results: A quantitative CD26/DPPIV plasma analysis from 100 HIV-R, 100 HIV infected (HIV +) and 100 HIV negative controls (HIV Neg) showed a significantly elevated CD26/DPPIV concentration among the HIV-R group (mean 1315 ng/ml) than the HIV Neg (910 ng/ml) and HIV + (870 ng/ml, p < 0.001). Similarly a FACs analysis of cell associated DPPIV (CD26) revealed a higher CD26/DPPIV expression on CD4+ T-cells derived from HIV-R than from the HIV+ (90.30% vs 80.90 p = 0.002) and HIV Neg controls (90.30% vs 82.30 p < 0.001) respectively. A further comparison of the mean fluorescent intensity (MFI) of CD26/DPPIV expression showed a higher DPP4 MFI on HIV-R CD4+ T cells (median 118 vs 91 for HIV-Neg, p = 0.0003). An evaluation for hyperglycemia, did not confirm Type 2 diabetes but an impaired fasting glucose condition (5.775 mmol/L). A follow-up quantitative PCR analysis of the insulin signaling pathway genes showed a down expression of NFκB, a central mediator of the immune response and activator of HIV-1 transcription., Conclusion: HIV resistant sex workers have a high expression of CD26/DPPIV in tandem with lowered immune activation markers. This may suggest a novel role for CD26/DPPIV in protection against HIV infection in vivo.

Studies of human immunodeficiency virus (HIV)-exposed seronegative individuals are crucial to inform vaccine design. In the present study we demonstrated that HIV-exposed seronegative commercial sex workers produce lower levels of proinflammatory cytokines at baseline than HIV-negative control subjects. We also showed that CD4+ T cells of HIV-exposed seronegative commercial sex workers have a characteristically lower level of gene expression that can be seen in differentially expressed genes and systems crucial for HIV replication, such as the T cell receptor pathway and previously identified HIV dependency factors. This apparent lowered activation results in a phenomenon we term "immune quiescence," which may contribute to host resistance to HIV.

Background: Antiretroviral therapy (ART) for HIV infection reconstitutes the immune system and improves survival. However, the rate and extent of CD4+ T cell recovery varies widely. We assessed the impact of several factors on immune reconstitution in a large Kenyan cohort., Methodology/principal Findings: HIV-infected female sex workers from a longitudinal cohort, with at least 1 year of pre-ART and 6 months of post-ART follow-up (n = 79), were enrolled in the current study. The median pre-ART follow-up was 4,040 days. CD4 counts were measured biannually and viral loads where available. The median CD4 count at ART initiation was 180 cells/ul, which increased to 339 cells/ul at the most recent study visit. The rate of CD4+ T cell increase on ART was 7.91 cells/month (mean = 13, range -25.92 to 169.4). LTNP status prior to ART initiation did not associate with the rate of CD4 recovery on ART. In univariate analyses, associations were observed for CD4 recovery rate and duration of pre-ART immunosuppression (r = -0.326, p = 0.004) and CD4 nadir (r = 0.284, p = 0.012). In multivariate analysis including age, CD4 nadir, duration of HIV infection, duration of pre-ART immunosuppression, and baseline viral load, only CD4 nadir (p = 0.007) and not duration of immunosuppression (p = 0.87) remained significantly associated with the rate of CD4 recovery., Conclusions/significance: These data suggest that prior duration of immune suppression does not predict subsequent recovery once ART is initiated and confirm the previous observation that the degree of CD4 depletion prior to ART initiation is the most important determinant of subsequent immune reconstitution.

Human immunodeficiency virus (HIV)-resistant commercial sex workers provide a unique opportunity to study correlates of protection associated with natural resistance to HIV infection. Emerging data from studies of these individuals and other uninfected individuals who have been exposed to HIV suggest that low levels of immune activation may contribute to protection against infection. In the present study, HIV-resistant individuals were shown to have reduced frequencies of T cells expressing the activation marker CD69. They were also found to have elevated frequencies of regulatory T (T(reg)) cells, compared with HIV-negative control individuals. By controlling levels of T cell activation, T(reg) cells may contribute to HIV resistance by minimizing the pool of cells susceptible to infection.

APOBEC3G is an important innate immune molecule that causes human immunodeficiency virus type 1 (HIV-1) hypermutation, which can result in detrimental viral genome mutations. The Vif protein of wild-type HIV-1 counteracts APOBEC3G activity by targeting it for degradation and inhibiting its incorporation into viral particles. Additional APOBEC cytidine deaminases have been identified, such as APOBEC3F, which has a similar mode of action but different sequence specificity. A relationship between APOBEC3F/G and HIV disease progression has been proposed. During HIV-1 sequence analysis of the vpu/env region of 240 HIV-infected subjects from Nairobi, Kenya, 13 drastically hypermutated proviral sequences were identified. Sequences derived from plasma virus, however, lacked hypermutation, as did proviral vif. When correlates of disease progression were examined, subjects with hypermutated provirus were found to have significantly higher CD4 counts than the other subjects. Furthermore, hypermutation as estimated by elevated adenine content positively correlated with CD4 count for all 240 study subjects. The sequence context of the observed hypermutation was statistically associated with APOBEC3F/G activity. In contrast to previous studies, this study demonstrates that higher CD4 counts correlate with increased hypermutation in the absence of obvious mutations in the APOBEC inhibiting Vif protein. This strongly suggests that host factors, such as APOBEC3F/G, are playing a protective role in these patients, modulating viral hypermutation and host disease progression. These findings support the potential of targeting APOBEC3F/G for therapeutic purposes.

Many factors can influence the rate of HIV disease progression, including those that maintain T cell homeostasis. One key homeostatic regulator is the IL-7 receptor (IL-7R). Previous studies have shown IL-7R expression levels decrease in HIV infection, but effects on memory subtypes, CD4(+) T cells, and cell function have not been explored. The present study examined the expression of the IL-7Ralpha chain on naïve and memory T lymphocyte subsets of both HIV-positive and HIV-negative individuals from Nairobi, Kenya to assess the role of IL-7Ralpha in HIV disease. Expression of IL-7Ralpha was significantly reduced in all CD4(+) and CD8(+) T cell subsets in HIV-positive individuals. This reduction was further enhanced in those with advanced HIV progression. Expression of IL-7Ralpha was inversely correlated to immune activation, and apoptosis, and was positively correlated with CD4 count in both bivariate and multivariate analysis. Expression of IL-7Ralpha did not correlate with HIV viral loads, indicating the elevated immune activation seen in HIV-infected individuals may be impacting expression of IL-7Ralpha, independent of viral loads. Signaling via the IL-7R is essential for T cell homeostasis and maintenance of T cell memory. Reduction of this receptor may contribute to the homeostatic disruption seen in HIV.

The immune response of human immunodeficiency virus (HIV)-exposed seronegative (ESN) women may be qualitatively different from that in those infected with HIV (HIV(+)). In a cohort of female commercial sex workers in Nairobi, Kenya, we found significantly lower (P< or =.01) levels of CD4(+)-specific immune activation and apoptosis in the ESN women compared with those in the HIV(+) women. Compared with the HIV(+) women, a lower proportion of the ESN women showed p24 peptide pool responses by the short-term, CD4(+)-specific, interferon (IFN)- gamma intracellular cytokine staining assay, whereas the proportion showing responses by the long-term, CD8(+)-depleted T cell proliferation assay was similar. Interestingly, the ESN responders had a 4.5-fold stronger proliferation response (P=.002) than the HIV(+) group. These data suggest that, compared with those in HIV(+) women, CD4(+) T cells in ESN women have a much greater ability to proliferate in response to p24 peptides.