Viral determinants of simian immunodeficiency virus (SIV) virulence in rhesus macaques assessed by using attenuated and pathogenic molecular clones of SIVmac

The intact cervicovaginal mucosa is a relative barrier to the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In the simian immunodeficiency virus (SIV) macaque model of HIV infection, seronegative transient viremia (STV; virus isolation positive followed by repeated negative cultures) occurs after intravaginal inoculation of a low dose of pathogenicSIVmac251 (C. J. Miller, M. Marthas, J. Torten, N. Alexander, J. Moore, G. Doncel, and A. Hendrickx, J. Virol. 68:6391-6400, 1994). Thirty-one adult female macaques that had been inoculated intravaginally with pathogenic SIVmac251 became transiently viremic. One monkey that had been culture negative for a year after SIV inoculation became persistently viremic and developed simian AIDS. No other STV monkey developed persistent viremia or disease. Results of very sensitive assays showed that 6 of 31 monkeys had weak SIV-specific antibody responses. SIV-specific antibodies were not detected in the cervicovaginal secretions of 10 STV monkeys examined. Twenty of 26 monkeys had lymphocyte proliferative responses to p55 gag and/or gp130 env antigens; 3 of 6 animals, including the monkey that became persistently viremic, had detectable cytotoxic T-lymphocyte (CTL) responses to SIV. At necropsy, lymphoid tissues and vaginal mucosa were virus culture negative, but in 10 of 10 animals, SIV provirus was detected by PCR using gag-specific primer pairs. Fifty percent of the PCR-positive tissue samples were also positive for SIV gag RNA by reverse transcriptase PCR. Thus, transient viremia following intravaginal inoculation of pathogenic SIV is associated with persistent, systemic infection, either latent or very low level productive. Atypical immune responses, characterized by lymphocyte proliferation and some CTL responses in the absence of conventionally detectable antibodies, develop in transiently viremic monkeys.

Section: Discussionmentioning

confidence: 99%

Occult Systemic Infection and Persistent Simian Immunodeficiency Virus (SIV)-Specific CD4⁺-T-Cell Proliferative Responses in Rhesus Macaques That Were Transiently Viremic after Intravaginal Inoculation of SIV

McChesney

Collins

Ding

et al. 1998

“…Unger et al found no difference between the replication kinetics of the nonpathogenic SIVmac1A11 and a nef deletion mutant of this virus (49). However, the 1A11 isolate is severely attenuated in vivo, and it is not known which regions of the 1A11 genome are responsible for its attenuation (31,32,49). Indeed, it is plausible that the nef gene of 1A11 is potentially functionally compromised compared with the SIVmac239open nef allele.…”

Section: Discussionmentioning

confidence: 99%

The nef gene products of both simian and human immunodeficiency viruses enhance virus infectivity and are functionally interchangeable

Sinclair

Barbosa

Feinberg

1997

Adult rhesus macaques infected with nef-defective simian immunodeficiency virus (SIV) exhibit extremely low levels of steady-state virus replication, do not succumb to immunodeficiency disease, and are protected from experimental challenge with pathogenic isolates of SIV. Similarly, rare humans found to be infected with nef-defective human immunodeficiency virus type 1 (HIV-1) variants display exceptionally low viral burdens and do not show evidence of disease progression after many years of infection. HIV-1 Nef induces the rapid endocytosis and lysosomal degradation of cell surface CD4 and enhances virus infectivity in primary human T cells and macrophages. Although expression of SIV Nef also leads to down-modulation of cell surface CD4levels, no evidence for SIV Nef-induced enhancement of virus infectivity was observed in earlier studies. Thus, it remains unclear whether fundamental differences exist between the activities of HIV-1 and SIV Nef. To establish more clearly whether the SIV and HIV-1 nef gene products are functionally analogous, we compared the replication kinetics and infectivity of variants of SIVmac239 that either do (SIVnef؉) or do not (SIV⌬nef) encode intact nef gene products. SIVnef؉ replicates more rapidly than nef-defective viruses in both human and rhesus peripheral blood mononuclear cells (PBMCs). As previously described for HIV-1 Nef, SIV Nef also enhances virus infectivity within each cycle of virus replication. As a strategy for evaluating the in vivo contribution of HIV-1 nef alleles and long terminal repeat regulatory sequences to the pathogenesis of immunodeficiency disease, we constructed SIV-HIV chimeras in which the nef coding and U3 regulatory regions of SIVmac239 were replaced by the corresponding regions from HIV-1/R73 (SIVR7nef؉). SIVR7nef؉ displays enhanced infectivity and accelerated replication kinetics in primary human and rhesus PBMC infections compared to its nef-defective counterpart. Converse chimeras, containing SIV Nef in an HIV-1 background (R7SIVnef؉) also exhibit greater infectivity than matched nef-defective viruses (R7SIV⌬nef). These data indicate that SIV Nef, like that of HIV-1, does enhance virus replication in primary cells in tissue culture and that HIV-1 and SIV Nef are functionally interchangeable in the context of both HIV-1 and SIV.

“…Alternatively, development of disease may involve a mixture of viral quasispecies rather than a particular viral strain, perhaps in agreement with the lack of selection of particular EIAV PV quasispecies during the initial stages of infection and disease as observed here. Studies using chimeras between nonpathogenic and pathogenic molecular clones of simian immunodeficiency virus indicate that although the env gene is an important determinant of pathogenesis, it is not the only determinant (20,26). These results indicate that other portions of the EIAV genome should be assessed for their roles in pathogenesis.…”

Section: Fig 5 Infection Of Equine Monocytes With Parental and Chimmentioning

confidence: 99%

Genomic quasispecies associated with the initiation of infection and disease in ponies experimentally infected with equine infectious anemia virus

Lichtenstein

Issel

Montelaro

1996

Equine infectious anemia virus (EIAV) provides a uniquely dynamic system in which to study the mechanism and role of genomic variation in lentiviral persistence and pathogenesis. We have used a Shetland pony model of infection to investigate the association of specific long terminal repeat (LTR) and env gene genomic sequences with the initiation of infection and the onset of disease. We analyzed viral RNA isolated from a pathogenic stock of virus (EIAV PV ) and from plasma taken during the first disease episode from two ponies infected with EIAV PV . Overall sequence variation within gp90 was low in EIAV PV and only slightly higher in plasma virus samples isolated from ponies during the first disease episode. However, a high proportion of mutations were localized to the principal neutralizing domain in EIAV PV and to the principal neutralizing domain and the gp90 hypervariable region in the two pony-derived samples. The rate of fixation of mutations was analyzed and determined to be approximately 4 ؋ 10 ؊2 mutations per site per year. Sequence diversity within the U3 region of the LTR was extremely low, which suggested that the previously reported hypervariability of this region may be a consequence of selection for replication of EIAV in different host cells. The predominant EIAV PV env and LTR sequences were used to construct chimeric viruses so that the contribution of these sequences to viral pathogenicity could be examined. The chimeras replicated in cultured equine monocytes to the same extent as the parental nonpathogenic virus and did not cause disease in Shetland ponies by 120 days postinfection, suggesting that the EIAV genomic determinants of pathogenesis are complex.