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HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.

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Feline leukemia virus (FeLV) is a common naturally occurring gammaretrovirus of domestic cats that is associated with degenerative diseases of the hematopoietic system, immunodeficiency, and neoplasia. Although the majority of cats exposed to FeLV develop a transient infection and recover, a proportion of cats become persistently viremic and many subsequently develop fatal diseases. To define the dominant host immune effector mechanisms responsible for the outcome of infection, we studied the longitudinal changes in FeLVspecific cytotoxic T lymphocytes (CTLs) in a group of naïve cats following oronasal exposure to FeLV. Using 51 Cr release assays to measure ex vivo virus-specific cytotoxicity, the emerging virus-specific CTL response was correlated with modulations in viral burden as assessed by detection of infectious virus, FeLV p27 capsid antigen, and proviral DNA in the blood. High levels of circulating FeLV-specific effector CTLs appeared before virus neutralizing antibodies in cats that recovered from exposure to FeLV. In contrast, persistent viremia was associated with a silencing of virus-specific humoral and cell-mediated host immune effector mechanisms. A single transfer of between 2 ؋ 10 7 and 1 ؋ 10 8 autologous, antigen-activated lymphoblasts was associated with a downmodulation in viral burden in vivo. The results suggest an important role for FeLV-specific CTLs in retroviral immunity and demonstrate the potential to modulate disease outcome by the adoptive transfer of antigen-specific T cells in vivo.

Summary Feline leukaemia virus (FeLV) nucleic acid vaccination of domestic cats affords protection against viraemia and the development of latency without inducing antiviral antibodies. 1 To determine the contribution of cell‐mediated immunity to the control of virus replication and clearance from the host, FeLV‐specific cytotoxic T lymphocyte (CTL) responses were compared in vaccine‐protected, transiently viraemic, and persistently viraemic cats. Vaccinal immunity was associated with the detection of higher levels of virus‐specific effector CTL in the peripheral blood and lymphoid organs to FeLV Gag/Pro and Env antigens than those observed in unvaccinated control, persistently viraemic cats (P < 0·001). Likewise, higher levels of virus‐specific CTLs were also observed in transiently viraemic cats which recovered following exposure to FeLV. In cats that controlled their infection, recognition of Gag/Pro antigens was significantly higher than the recognition of Env antigens. This is the first report highlighting the very significant role that virus‐specific CTL have in determining the outcome of FeLV infection in either vaccinated cats or cats recovering naturally from FeLV exposure.

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Definition of the immunological mechanisms involved in protective immunity against lentiviral infections is crucial to the development of an effective vaccine. The induction of gag- and env-specific cell-mediated immune responses was studied in cats following vaccination with whole inactivated feline immunodeficiency virus (FIV). Cats were immunized by inoculation with three doses of paraformaldehyde-inactivated FIV, derived from the feline lymphoid cell line, FL-4, which is persistently infected with the Petaluma isolate of FIV. Autologous or allogeneic skin fibroblasts either infected with recombinant FIV gag- or env-vaccinia virus or pulsed with FIV env peptides were used as targets in chromium-51 release assays. Effector cells were fresh peripheral blood mononuclear cells. Following the third immunization, all vaccinated cats, but none of the control cats immunized with adjuvant alone, had detectable FIV env-specific lymphocytotoxicity in their peripheral blood. Two cats also exhibited gag-specific activity. There was no recognition of either allogeneic skin fibroblasts infected with recombinant vaccinia virus or autologous target cells infected with wild-type vaccinia virus, indicating the specificity and MHC-restricted nature of the response. Vaccinated cats, but not control cats, were protected from challenge with the homologous Petaluma isolate of FIV. Partial epitope mapping of the env-specific cytotoxic response was performed using overlapping 10-amino acid peptides from the env V3 domain of FIV. This response appeared to be directed at env peptide 1 (RAISSWKQRN) and env peptide 3 (QRNRWEWRPD), which lie adjacent to a beta-turn within the V3 domain.(ABSTRACT TRUNCATED AT 250 WORDS)

Adherence to once daily abacavir/lamivudine was good with no evidence of an association between nonadherence and virologic rebound. Acceptability of once daily drugs was best when the whole regimen was dosed once daily.