Pathogenesis Studies Of Simian Immunodeficiency Virus Infection Of Monkeys

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Abstract

An experimental animal model in which the course of immunodeficiency virus infection parallels the pathogenesis of the human disease is critical for the study of human AIDS. Simian immunodeficiency virus (SIV) infection of macaques satisfies this criterion and is therefore a relevant model. SIV induces an immunodeficiency syndrome in infected macaques that is remarkably similar in pathogenesis to human AIDS. An important use of this animal model system is the detailed study of pathogenesis and viral determinants of disease since many studies of this type are not feasible in humans. The purpose of this project is to investigate host and viral factors involved in variable disease progression in SIV-infected macaques and the lack of disease in African primates infected with their own strains of SIV. [unreadable] [unreadable] PATHOGENESIS OF SIVsm-INFECTION OF MACAQUES:[unreadable] To investigate the role of host factors in SIV-infection of macaques, we used a well-defined molecularly cloned virus (SIVsmE543-3). In vitro susceptibility of primary PBMC to SIV infection varies between donor macaques and correlates with the extent of viral replication following in vivo inoculation. However, although macaques with low susceptibility phenotype initially maintained low levels of viremia for variable periods of time, eventual progression to AIDS was observed coincident with increasing viremia, suggesting viral and/or immune escape in these animals. [unreadable] [unreadable] Our initial studies have focused on defining the immune and viral factors involved in the development of rapid disease progression. This small subset of SIV-infected macaques fails to maintain SIV-specific immune responses and progress to AIDS in less than six months from the time of inoculation. SIVsmE543-3-infected RP macaques showed profound and irreversible depletion of memory CD4+ T cells that likely explain the immune deficits in these animals. [unreadable] [unreadable] Molecular studies of virus in tissues and plasma of rapid progressor macaques exhibited common substitutions in the env gene. These substitutions were unusual in that they involved residues that were generally conserved and that were known to affect binding of env to CD4 or coreceptor. Virus from RP macaques was molecularly and biologically characterized. Full length infectious molecular clones of various RP viruses were derived from plasma of RP inoculated with virus isolated from tissues of one of the initial RP study animals. The H635 viruses replicated less efficiently in primary macaque PBMC and macrophages than the parental SIVsmE543-3 strain. However, macaques inoculated with one of these viruses, H635-FC developed moderate to high primary and setpoint viremia, and progressive CD4+ T cell depletion. Sequence analysis of plasma virus in these animals demonstrated rapid loss of RP-specific env mutations as well as progressive development of heterogeneity. Coinoculation of rhesus with 543 and FC clones resulted in pathogenic infection with rapid disease in one of three macaques. Interestingly, 543 and FC viruses were equally represented in plasma during primary infection but 543 predominated later.[unreadable] [unreadable] Previous studies in this lab demonstrated that infection of PT macaques with SIVagm9063 results in AIDS. We assessed the pathogenicity of the SIVagm9063 and two primary SIVagm isolates in PT macaques. Infection of macaques with any of the three isolates resulted in high levels of primary plasma viremia by one week after inoculation. Viremia was quickly controlled following infection with SIVagm155; these animals have maintained CD4+ T cell subsets and remain healthy. The plateau levels among SIVagm90 and SIVagm9063-inoculated macaques varied widely from 100 to a million copies/ml of plasma. Three of four animals from each of these groups progressed to AIDS. Setpoint viremia and the degree of CD4+ T cell loss at six months post infection were not significantly different between macaques inoculated with SIVagm90 and SIVagm9063. However, these parameters were significantly different in SIVagm155-inoculated macaques (p values < 0.01). Considering all the macaques, the degree of CD4+ T cell loss by six months post infection, correlated with the plateau levels of viremia. Thus, similar to SIVsm/mac-infection of macaques and human AIDS, viral load is an excellent prognostic indicator of disease course.[unreadable] [unreadable] ASYMPTOMATIC INFECTION OF NATURAL HOST SPECIES[unreadable] A second goal of this project is to study the mechanisms underlying the lack of pathogenicity of SIV for their natural host species, with emphasis on SIVagm from vervet monkeys. SIVsm, SIVagm and SIVlhoest are capable of inducing AIDS in macaques but are not virulent for their natural host. We evaluated the viral kinetics of a natural SIVagm isolate in AGM. Two species of AGM were evaluated, vervet monkeys (the species of origin of SIVagm90) and sabaeus monkeys from the Barbados. The virologic outcome in sabaeus and vervet AGM was surprisingly divergent. Inoculation of sabaeus AGM with SIVagm90 resulted in low and variable levels of primary viremia and low setpoints (< 100 to 10,000 copies/ml). In contrast, inoculation of vervet AGM resulted in high primary viremia and establishment of moderate plateau levels (10,000 to 100,000). Regardless of the extent of viremia, CD4+ T lymphocytes remained stable throughout infection of AGM with no significant relationship between viral load and CD4+ T cell loss.