Temporal Dynamics of CD8+ T Cell Effector Responses during Primary HIV Infection.

The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion. As infection progressed expression of perforin was maintained in HIV-specific CD8+ T cells with high levels of T-bet, but not necessarily in the population of T-betLo HIV-specific CD8+ T cells that expand as infection progresses. Together, these data demonstrate that while HIV-specific CD8+ T cells in acute HIV infection initially possess cytolytic potential, progressive transcriptional dysregulation leads to the reduced CD8+ T cell perforin expression characteristic of chronic HIV infection.

CD8(+) T-cell effector function and transcriptional regulation during HIV pathogenesis.

A detailed understanding of the immune response to human immunodeficiency virus (HIV) infection is needed to inform prevention and therapeutic strategies that aim to contain the acquired immunodeficiency syndrome (AIDS) pandemic. The cellular immune response plays a critical role in controlling viral replication during HIV infection and will likely need to be a part of any vaccine approach. The qualitative feature of the cellular response most closely associated with immunological control of HIV infection is CD8(+) T-cell cytotoxic potential, which is responsible for mediating the elimination of infected CD4(+) T cells. Understanding the underlying mechanisms involved in regulating the elicitation and maintenance of this kind of effector response can provide guidance for vaccine design. In this review, we discuss the evidence for CD8(+) T cells as correlates of protection, the means by which their antiviral capacity is evaluated, and transcription factors responsible for their function, or dysfunction, during HIV infection.

A radiolabeled oligonucleotide ligation assay demonstrates the high frequency of nevirapine resistance mutations in HIV type 1 quasispecies of NVP-treated and untreated mother-infant pairs from Uganda.

This study explores the levels of NVP and AZT resistance mutations in untreated, NVP- or AZT-treated mother-infant pairs in Uganda. PCR-amplified reverse transcriptase (RT) gene fragments derived from PBMC samples of 85 mothers (10 AZT treated, 35 NVP treated, and 40 untreated) and their 52 infected infants (5 AZT, 9 NVP, and 38 untreated) were classified as subtype A (59%), D (29%), C (3%), and recombinant forms (9%) by population sequencing. Only 16% of the NVP-treated infected mothers and infants harbored either the K103N or the Y181C at 6 weeks postdelivery. The majority of these samples (n = 107) were then analyzed using a radiolabeled oligonucleotide ligation assay (OLA) specific for K70R, K103N, and Y181C, using nonstandard bases to accommodate sequence heterogeneity. By OLA, 43% of the NVP-treated group had K103N and/or Y181C mutations in their HIV-1 population, using >0.6% cutoff based on a comparative clonal analysis of clinical isolates. Surprisingly, an equal fraction of the untreated and NVP-treated mother-infant group had the K103N mutation in their HIV-1 population in the range of 0.6-5%. These findings suggest a relatively high frequency of K103N mutation in the drug-naive, subtype A and D infected Ugandan population as compared to the very low frequency of the Y181C and K70R mutation (<0.6%). The prevalence of the K103N mutations may be related to its low fitness cost and high genetic stability. The persistence of these mutations may reduce the effectiveness of subsequent NVP use in treatment or prevention of perinatal transmission.