Escape from specific T-cell responses contributes to the progression of human immunodeficiency virus type 1 (HIV-1) infection. T-cell escape viral variants are retained following HIV-1 transmission between major histocompatibility complex (MHC)-matched individuals. However, reversion to wild type can occur following transmission to MHC-mismatched hosts in the absence of cytotoxic T-lymphocyte (CTL) pressure, due to the reduced fitness of the escape mutant virus. We estimated both the strength of immune selection and the fitness cost of escape variants by studying the rates of T-cell escape and reversion in pigtail macaques. Near-complete replacement of wild-type with T-cell escape viral variants at an immunodominant simian immunodeficiency virus Gag epitope KP9 occurred rapidly (over 7 days) following infection of pigtail macaques with SHIV SF162P3 . Another challenge virus, SHIV mn229 , previously serially passaged through pigtail macaques, contained a KP9 escape mutation in 40/44 clones sequenced from the challenge stock. When six KP9-responding animals were infected with this virus, the escape mutation was maintained. By contrast, in animals not responding to KP9, rapid reversion of the K165R mutation occurred over 2 weeks after infection. The rapidity of reversion to the wild-type sequence suggests a significant fitness cost of the T-cell escape mutant. Quantifying both the selection pressure exerted by CTL and the fitness costs of escape mutation has important implications for the development of CTL-based vaccine strategies.

Mucosal-associated invariant T (MAIT) cells home to mucosal sites and exert antimicrobial activity against bacteria and other microorganisms. HIV infection leads to early depletion of gut T cells and translocation of bacterial products. There are reports that MAIT cells, defined by coexpression of Vα7.2 and CD161, are depleted during HIV infection and residual MAIT cells are functionally impaired. However, one study suggested that MAIT cells might remain after HIV infection but evade detection through CD161 downregulation. Thus, the impact of HIV infection on MAIT cells is unclear. We studied longitudinal blood samples from 31 HIV-infected subjects for MAIT cell numbers, phenotype and function using both standard Vα7.2/CD161 surface markers and an MR1 tetramer. We found that MAIT cells were depleted early during HIV infection, and although there was a concomitant rise in Vα7.2(+)CD161(-) cells, these were MR1 tetramer negative, indicating that these are unlikely to be altered MAIT cells. Antigen-mediated activation of residual MAIT cells showed that they remained functional out to 2 years following HIV infection. Although MAIT cells are depleted in HIV infection, residual and functionally active MAIT cells persist and may still be able to assist in controlling bacterial translocation during HIV infection.

Successful human immunodeficiency virus (HIV) vaccines will need to induce effective T-cell immunity.We studied immunodominant simian immunodeficiency virus (SIV) Gag-specific T-cell responses and their restricting major histocompatibility complex (MHC) class I alleles in pigtail macaques (Macaca nemestrina), an increasingly common primate model for the study of HIV infection of humans. CD8؉ T-cell responses to an SIV epitope, Gag 164-172 KP9, were present in at least 15 of 36 outbred pigtail macaques. The immunodominant KP9-specific response accounted for the majority (mean, 63%) of the SIV Gag response. Sequencing from six macaques identified 7 new Mane-A and 13 new Mane-B MHC class I alleles. One new allele, Mane-A*10, was common to four macaques that responded to the KP9 epitope. We adapted reference strand-mediated conformational analysis (RSCA) to MHC class I genotype M. nemestrina. Mane-A*10 was detected in macaques presenting KP9 studied by RSCA but was absent from non-KP9-presenting macaques. Expressed on class I-deficient cells, Mane-A*10, but not other pigtail macaque MHC class I molecules, efficiently presented KP9 to responder T cells, confirming that Mane-A*10 restricts the KP9 epitope. Importantly, naïve pigtail macaques infected with SIV mac251 that respond to KP9 had significantly reduced plasma SIV viral levels (log 10 0.87 copies/ml; P ‫؍‬ 0.025) compared to those of macaques not responding to KP9. The identification of this common M. nemestrina MHC class I allele restricting a functionally important immunodominant SIV Gag epitope establishes a basis for studying CD8 ؉ T-cell responses against AIDS in an important, widely available nonhuman primate species.

Human herpesvirus (HHV)-6 and HHV-7 loads were evaluated retrospectively in peripheral blood mononuclear cells (PBMC) from 78 recipients of stem cell transplantation (SCT) by real-time polymerase chain reaction. The median HHV-6 load in patients was 1357 genome equivalent copies (EqCop)/10(6) PBMC but was below the quantitation threshold in 31 immunocompetent individuals, which strongly suggests that HHV-6 reactivation occurred after SCT. The HHV-6 load was higher in patients with delayed neutrophil engraftment (P=.002) or severe graft-versus-host disease (P=.009). Moreover, the occurrence of at least 1 HHV-6-related manifestation (fever, cutaneous rash, pneumonitis, or partial myelosuppression) was statistically associated with a concomitant virus load >10(3) EqCop/10(6) PBMC (P=.007). Conversely, HHV-7 reactivation was not favored, because median HHV-7 loads were similar in patients and healthy control subjects (1053 vs. 1216 EqCop/10(6) PBMC). The kinetics of Roseolovirus loads during the posttransplantation period suggested that HHV-7 may act as a cofactor of HHV-6 reactivation.