Summary Preclinical studies of HIV-1 vaccine candidates have typically shown post-infection virologic control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges1–3. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant virus challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing SIVsmE543 Gag, Pol, and Env antigens resulted in a ≥80% reduction in the per-exposure probability of infection4,5 against repetitive, intrarectal SIVmac251 challenges in rhesus monkeys. Protection against acquisition of infection exhibited distinct immunologic correlates as compared with post-infection virologic control and required the inclusion of Env in the vaccine regimen. These data demonstrate the first proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.

Prior studies demonstrated that immunization of macaques with simian immunodeficiency virus (SIV)Gag

Summary The viral accessory protein Vpx, expressed by certain simian and human immunodeficiency viruses (SIVs and HIVs), is thought to improve viral infectivity of myeloid cells. We infected 35 Asian macaques and African green monkeys with viruses that do or do not express Vpx, and examined viral targeting of cells in vivo. While lack of Vpx expression affected viral dynamics in vivo, with decreased viral loads and infection of CD4+ T cells, Vpx expression had no detectable effect on infectivity of myeloid cells. Moreover, viral DNA was only observed within myeloid cells in tissues not massively depleted of CD4+ T-cells. Myeloid cells containing viral DNA also showed evidence of T cell phagocytosis in vivo, suggesting their viral DNA may be attributed to phagocytosis of SIV-infected T cells. These data suggest that myeloid cells are not a major source of SIV in vivo, irrespective of Vpx expression.

The distribution and levels of simian immunodeficiency virus (SIV) in tissues and plasma were assessed in naturally infected African green monkeys (AGM) of the vervet subspecies (Chlorocebus pygerythrus) by limitingdilution coculture, quantitative PCR for viral DNA and RNA, and in situ hybridization for SIV expression in tissues. A wide range of SIV RNA levels in plasma was observed among these animals (<1,000 to 800,000 copies per ml), and the levels appeared to be stable over long periods of time. The relative numbers of SIV-expressing cells in tissues of two monkeys correlated with the extent of plasma viremia. SIV expression was observed in lymphoid tissues and was not associated with immunopathology. Virus-expressing cells were observed in the lamina propria and lymphoid tissue of the gastrointestinal tract, as well as within alveolar macrophages in the lung tissue of one AGM. The range of plasma viremia in naturally infected AGM was greater than that reported in naturally infected sooty mangabeys. However, the degree of viremia in some AGM was similar to that observed during progression to AIDS in human immunodeficiency virus-infected individuals. Therefore, containment of viremia is an unlikely explanation for the lack of pathogenicity of SIVagm in its natural host species, AGM. Human immunodeficiency virus type 1 (HIV-1) is a member of a large family of nonhuman primate lentiviruses which have been designated simian immunodeficiency viruses (SIVs). At the present time, SIVs from at least seven African monkey species have been identified and molecularly characterized. The genetic relationships among five of these SIV strains isolated from sooty mangabey monkeys (Cercocebus atys; SIVsm), mandrills (Mandrillus sphinx; SIVmnd), Sykes monkeys (Cercopithecus albogularis mitis; SIVsyk), African green monkeys, (AGM; Chlorocebus spp.; SIVagm), and chimpanzees (Pan troglodytes; SIVcpz) have been reviewed previously (23,25,44). Briefly, SIV isolates segregate phylogenetically, based upon their species of origin, into at least five lineages represented by SIVsm, SIVagm, SIVsyk, SIVlhoest (9,26), and SIVcpz with a number of additional novel strains from other primates recently characterized (12,18). The SIVagm lineage consists of four distinct subtypes that cluster depending upon the species of AGM from which they were isolated, i.e

The immunogenicity and protective efficacy of a modified vaccinia virus Ankara (MVA) recombinant expressing the simian immunodeficiency virus (SIV) Gag-Pol proteins (MVA-gag-pol) was explored in rhesus monkeys expressing the major histocompatibility complex (MHC) class I allele, MamuA*01. Macaques received four sequential intramuscular immunizations with the MVA-gag-pol recombinant virus or nonrecombinant MVA as a control. Gag-specific cytotoxic T-lymphocyte (CTL) responses were detected in all MVA-gagpol-immunized macaques by both functional assays and flow cytometric analyses of CD8 ؉ T cells that bound a specific MHC complex class I-peptide tetramer, with levels peaking after the second immunization. Following challenge with uncloned SIVsmE660, all macaques became infected; however, viral load set points were lower in MVA-gag-pol-immunized macaques than in the MVA-immunized control macaques. MVA-gag-pol-immunized macaques exhibited a rapid and substantial anamnestic CTL response specific for the p11C, C-M Gag epitope. The level at which CTL stabilized after resolution of primary viremia correlated inversely with plasma viral load set point (P ‫؍‬ 0.03). Most importantly, the magnitude of reduction in viremia in the vaccinees was predicted by the magnitude of the vaccine-elicited CTL response prior to SIV challenge.Evidence for a critical role of cytotoxic T lymphocytes (CTLs) in the containment of human immunodeficiency virus (HIV) infection (16,23,36,39) has led to a consensus among those attempting to develop an AIDS vaccine that such a vaccine should generate CTL in addition to broadly neutralizing antibodies (26). An additional hurdle for an AIDS vaccine is the long-term maintenance of levels of CTL and antibody that will be necessary for protection (26). Both effector CTL and neutralizing antibodies induced by vaccination tend to be transient. Therefore, it may not be feasible to maintain immune responses essential for preventing infection. The importance of the magnitude of the vaccine-elicited memory and postinfection anamnestic immune responses thus become a critical issue in developing an AIDS vaccine.At present, viable vaccine strategies that might effectively stimulate CTL include viral vectors, peptides, and DNA immunization (26). Viral vectors under investigation include adenovirus (10, 48), alphaviruses such as Semliki Forest virus (8, 35) and Venezuelan equine encephalitis virus (11), poliovirus replicons (23), and various poxviruses (12,21,29,30,34,43). Among these approaches, use of the poxviruses is a particularly promising vaccine strategy to express viral proteins. Studies with conventional New York Board of Health vaccinia virus demonstrated that priming with a vaccinia virus recombinant expressing simian immunodeficiency virus (SIV) envelope and/or core proteins, followed by boosting the antibody response with recombinant envelope protein, provided protection against a homologous SIV challenge with a biologically cloned strain of limited pathogenicity (SIVmne/E11S) (20). However this app...