Concordance of immunological events between intrarectal and intravenous SHIVAD8-EO infection when assessed by Fiebig-equivalent staging.

Primary HIV-1 infection can be classified into six Fiebig stages based on virological and serological laboratory testing, whereas simian-HIV (SHIV) infection in nonhuman primates (NHPs) is defined in time post-infection, making it difficult to extrapolate NHP experiments to the clinics. We identified and extensively characterized the Fiebig-equivalent stages in NHPs challenged intrarectally or intravenously with SHIVAD8-EO. During the first month post-challenge, intrarectally challenged monkeys were up to 1 week delayed in progression through stages. However, regardless of the challenge route, stages I-II predominated before, and stages V-VI predominated after, peak viremia. Decrease in lymph node (LN) CD4+ T cell frequency and rise in CD8+ T cells occurred at stage V. LN virus-specific CD8+ T cell responses, dominated by degranulation and TNF, were first detected at stage V and increased at stage VI. A similar late elevation in follicular CXCR5+ CD8+ T cells occurred, consistent with higher plasma CXCL13 levels at these stages. LN SHIVAD8-EO RNA+ cells were present at stage II, but appeared to decline at stage VI when virions accumulated in follicles. Fiebig-equivalent staging of SHIVAD8-EO infection revealed concordance of immunological events between intrarectal and intravenous infection despite different infection progressions, and can inform comparisons of NHP studies with clinical data.

Protective correlates against HIVs may have evolved in human populations in the areas of historic occurrence of primate-to-man transmissions of SIVs ancestral to HIVs: studies in these populations may provide crucial insights for treatment and prevention of HIV infection.

Recent findings suggest that Human Immunodeficiency Viruses, HIV-1 and 2, might have been transmitted to humans from particular primate species. It is thought that some Simian Immunodeficiency Viruses (SIVs), from which HIVs presumably originated, existed in their primate hosts for ages. Behavioral characteristics increasing the probability of contact between these primates and humans (such as keeping monkeys for pets, hunting monkeys for food, improper handling of the monkey meat, etc.) documented in some African countries could have facilitated cross-species transmissions (CSTs) of HIVs. As it has been shown, multiple CSTs took place for both HIVs (1 and 2) and then, in a globalizing world, these local events led to the pandemic. Here, it is brought forward that in the regions of epizooty of SIVs closely related to HIVs, some human populations might have had exposure history to these viruses dating back hundreds years. Lacking the important framework for further spread provided by nowadays globalization, these CSTs could have led to isolated local HIV outbreaks limited to particular tribes or groups. The infections could have extinguished some populations while on the other hand provided evolutionary pressure to select for mechanisms protective for HIV infection and/or disease. Thus, here it is hypothesized that in the areas of the habitat of primates infected with SIVs, from which HIVs are thought to be originated, there could be historically exposed populations which might possess biological correlates of protection from HIVs. Current knowledge on the distribution of primates hosting HIV-related SIVs suggests that epidemiological, primatological, anthropological and molecular biological studies in the areas of Cameroon, Gabon, both Congos and Equatorial Guinea (for HIV-1) and Guinea-Bissau, Senegal, Guinea, Ivory Cost, Sierra Leone and Liberia (for HIV-2) could lead to the discoveries of correlates of protection against HIVs. It is also hypothesized that virology studies in the same areas might reveal less virulent and/or infective viruses which could provide insights in the HIV pathogenesis and vaccinology.

Phylogenetic analysis of SIV derived from mandrill and drill.

SIVmnd was isolated from mandrills in Gabon in 1989 soon after the existence of simian counterparts of HIV such as SIVmac and SIVagm was known. Since then the SIVmnd has been long considered as an independent SIV lineage and the natural host is the mandrill. However this initial finding turned out to be more complex by the recent finding of new SIV isolated from mandrills living in northern mandrill habitat, and other SIV isolated from drills and other species. One fact which made these findings complicated was the fact that the SIVmnd made a tight cluster with SIVlhoest and SIVsun from genus Cercopithecus, which is different from genus Mandrillus. A second fact is that the second SIVmnd isolates are different in the genomic structure from the former SIVmnd and almost similar to SIVdrl from drills, and phylogenetically closely related with each other. At present, the former SIVmnd isolate is termed SIVmnd-1 and the second SIVmnd isolate is called SIVmnd-2. Interestingly SIVmnd-2/SIVdrl has the same mosaic structure containing the vpx gene which is absent in SIVmnd-1. The mosaic structure was probably due to a recombination between SIVmnd-1 and SIVrcm from red capped mangabey (or similar viruses) having the vpx gene. However this recombination event is not recent, and SIVmnd-1, SIVmnd-2 and SIVdrl have been likely maintained for a long period of time in each species. In this article, we speculate on the origin and evolution of these SIVs.

Characterization of the pathogenic KU-SHIV model of acquired immunodeficiency syndrome in macaques.

By animal-to-animal passage in macaques we derived a pathogenic chimeric simian-human immunodeficiency virus (SHIV) that caused CD4+ T cell loss and AIDS in pigtail macaques and used it to inoculate 20 rhesus and pigtail macaques by the intravaginal and intravenous routes. On the basis of the outcome of infection and patterns of CD4+ T cell loss and viral load, disease was classified into four patterns: acute, subacute, chronic, and nonprogressive infection. During the study period, 15 of the 20 animals developed fatal disease, including AIDS, encephalitis, pneumonia, and severe anemia. Opportunistic pathogens identified in these animals included Pneumocystis, cytomegalovirus, Cryptosporidium, Toxoplasma, and Candida. No single parameter by itself predicted outcome, although a combination of low CD4+ T cell counts in blood, high plasma virus levels, and presence of autoantibodies to red blood cells reliably predicted a fatal outcome. Five animals (25%) died within 3 months of inoculation and constituted the group with acute disease, whereas the nine animals (45%) with subacute disease died between 3 and 8 months postinoculation. This 70% mortality within 8 months is significantly shorter than in HIV-1-infected human beings, of whom 70% develop fatal disease a decade after infection. SHIV infection in macaques provides a useful model with which to evaluate antiviral strategies, combining all the advantages of the SIVmac system, yet using a virus bearing the envelope gene of HIV-1.