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We coinfected rhesus macaques with CXC chemokine receptor 4- and CC chemokine receptor 5-specific simian/human immunodeficiency viruses (SHIVs) to elucidate the basis for the early dominance of R5-tropic strains seen in HIV-infected humans. We found no intrinsic barrier to the transmission and dissemination of high-dose X4-SHIV in the dually infected macaques. In animals that maintained a viral set point, the R5 virus predominated. The time of appearance of R5 dominance coincided with the development of virus-specific immunity (3-6 weeks postinfection), suggestive of differential immune control of the two viruses. Indeed, after depletion of CD8+ T cells in the coinfected animals, X4 virus emerged, supporting the concept that differential CD8+ T cell-mediated immune control of X4- and R5-SHIV replication is responsible for the selective outgrowth of R5 viruses. These findings provide critical insights into a key question related to HIV pathogenesis and have important implications for the development and testing of antiviral vaccines and therapeutics.

Through rapid serial transfer in vivo, the chimeric CCR5-tropic simian/human immunodeficiency virus SHIV(SF162) evolved from a virus that is nonpathogenic and poorly transmissible across the vaginal mucosa to a variant that still maintains CCR5 usage but which is now pathogenic and establishes intravaginal infection efficiently. To determine whether envelope glycoprotein gp120 is responsible for increased pathogenesis and transmissibility of the variant SHIV(SF162P3), we cloned and sequenced the dominant envelope gene (encoding P3 gp120) and characterized its functions in vitro. Chimeric SHIV(SF162) virus expressing P3 gp120 of the pathogenic variant, designated SHIV(SF162PC), was also constructed and assessed for its pathogenicity and mucosal transmissibility in vivo. We found that, compared to wild-type SHIV(SF162) gp120, P3 gp120 conferred in vitro neutralization resistance and increased entry efficiency of the virus but was compromised in its fusion-inducing capacity. In vivo, SHIV(SF162PC) infected two of two and two of three rhesus macaques by the intravenous and intravaginal routes, respectively. Nevertheless, although peak viremia reached 10(6) to 10(7) RNA copies per ml of plasma in some infected animals and was associated with depletion of gut-associated CD4(+) lymphocytes, none of the animals maintained a viral set point that would be predictive of progression to disease. Together, the data from this study suggest a lack of correlation between entry efficiency and cytopathic properties of envelope glycoproteins with viral pathogenicity. Furthermore, whereas env gp120 contains the determinant for enhanced mucosal transmissibility of SHIV(SF162P3), the determinant(s) of its increased virulence may require additional sequence changes in env gp41 and/or maps to other viral genes.

Infection of rhesus macaques with chimeric simian-human immunodeficiency viruses (SHIV) is an established model to study acquired immunodeficiency syndrome (AIDS) pathogenesis. Such a controlled system allows for detailed analysis of the molecular determinants of viral pathogenesis in addition to studying host-specific immune responses that modulate disease progression. Furthermore, the use of a pathogenic molecular clone affords the opportunity to study both viral evolution within a host and to examine the generation of tissue specific variants. In this report we describe viral diversification within tissues of two rhesus macaques infected intravenously with the CXCR4-specific molecular clone SHIVSF33A2. Heteroduplex tracking analysis (HTA) was used to determine the complexity of viral DNA within distinct lymphoid tissues. Not surprising, heterogeneity of the proviral quasispecies in tissues obtained during the acute infection was limited. However, tissues obtained at necropsy harbored a more diverse and often different population of env variants. As the inoculating virus is a molecular clone, the variants generated are likely due to the presence of tissue specific selective forces rather than a founder's effect.

Infection of macaques with chimeric simian/human immunodeficiency virus (SHIV) expressing the envelope protein of HIV-1 provides a model system for studying HIV-1 infection in humans. To this end, four rhesus macaques (Macaca mulatta) were given a single intravaginal (IVAG) inoculation of cell-free SHIVSF33A and longitudinal samples of peripheral blood and lymph nodes were analyzed for viremia, antigenemia, and various T-cell populations. Rhesus macaques infected IVAG with SHIVSF33A demonstrated a dramatic decrease in the CD4(+) PBMC subset in the initial weeks after viral exposure, a time that corresponded to peak in plasma viremia and antigenemia. Within 4 months of SHIVSF33A inoculation, partial to complete rebound of the CD4(+) PBMC was seen in these animals. Notably, the regeneration of the CD4(+) subset was associated with regeneration of the naive T-cell population and was concordant with clearance of plasma viremia. DNA heteroduplex tracking assays revealed transmission of minor variants within the SHIVSF33A inoculum to the IVAG-inoculated animals. The cell-free SHIVSF33A inoculum as well as virus isolated from animals early after transmission used the chemokine molecule CXCR4 as the primary cellular coreceptor, demonstrating that viruses expressing envelope glycoproteins of the syncytia inducing (SI) phenotype can be transported across the vaginal mucosa. Although none of the animals has yet to develop clinical symptoms of simian AIDS (SAIDS), infectious virus and viral nucleic acids could be persistently isolated from each animal. Furthermore, animals transfused with blood from IVAG-infected macaques drawn 2 weeks after inoculation suffered a more profound and sustained CD4(+) T-cell loss, persistent plasma viremia, and the development of SAIDS in one animal, indicating that IVAG-passaged SHIVSF33A was pathogenic. Taken together, these results establish that a pathogenic CXCR4-utilizing SHIVSF33A species crossed the cervicovaginal mucosa. Different courses of infection in the IVAG versus transfusion animals suggest that host-mediated responses elicited upon transmission across mucosal barriers may serve to limit viral replication and delay disease progression in the IVAG-infected animals., (Copyright 1998 Academic Press.)

The human immunodeficiency virus (HIV) penetrates the central nervous system, particularly the cerebrospinal fluid, early in the course of HIV infection, and may cause a progressive encephalopathy in patients prior to the development of the acquired immunodeficiency syndrome. Neither the specific mechanism for penetration of the virus into the central nervous system nor the pathophysiological basis for these abnormalities is well understood. We cultured cells from the choroid plexus of 3 individuals who died of causes unrelated to the acquired immunodeficiency syndrome and demonstrated that these cells can be infected with type 1 HIV. Infection of cells of the choroid plexus may provide an initial route of entry of HIV into the cerebrospinal fluid and, together with the macrophage, a route of entry into the brain.