Characterization of molecularly cloned simian-human immunodeficiency viruses causing rapid CD4+ lymphocyte depletion in rhesus monkeys

Abstract

In vivo passage of a chimeric simian-human immunodeficiency virus (SHIV-89.6) expressing the human immunodeficiency virus type 1 (HIV-1) tat, rev, vpu, and env genes generated pathogenic viruses (SHIV-89.6P) inducing rapid CD4+ lymphocyte depletion and AIDS-like illness in rhesus monkeys (K. Reimann, J. T. Li, R. Veazey, M. Halloran, I.-W. Park, G. B. Karlsson, J. Sodroski, and N. L. Letvin, J. Virol. 70:6922-6928, 1996). To characterize the molecular changes responsible for this increase in virulence, infectious proviral clones of SHIV-89.6P isolates were derived. Viruses generated from some of these clones caused a rapid and profound decline of CD4+ lymphocytes in a high percentage of inoculated monkeys. Nucleotide changes potentially responsible for the increased virulence of SHIV-89.6P were limited to the env, tat, or long terminal repeat sequences, with most of the observed changes in env. Nucleotide changes in env altered 12 amino acids in the gp120 and gp41 exterior domains, and a 140-bp deletion in env resulted in the substitution of the carboxyl terminus of the SIVmac gp41 glycoprotein for that of the HIV-1 gp41 glycoprotein. The availability of pathogenic proviral clones should facilitate dissection of the molecular determinants of SHIV-89.6P virulence.

The Envelope Glycoprotein Ectodomains Determine the Efficiency of CD4+ T Lymphocyte Depletion in Simian– Human Immunodeficiency Virus–Infected Macaques

“…2 A). Consistent with previously published results (34), all monkeys inoculated with SHIV-KB9 exhibited severely depressed CD4 ϩ lymphocyte levels, ranging from 30 to 220 cells per l of blood by 14 d after infection. Animals inoculated with SHIV-89.6* showed no persistent loss of CD4 ϩ T cells, indicating that the passageassociated tat and LTR changes are not sufficient to cause CD4 ϩ T lymphocyte depletion.…”

“…The proviral structures of the SHIV variants used in this study are depicted beneath. SHIV-89.6* is identical to the parental SHIV-89.6, except that it contains the passage-associated tat and LTR changes (34). The other three variants differ from SHIV-89.6* only in the sequence of the envelope glycoproteins.…”

Chronic immune stimulation accelerates SIV‐induced disease progression

“…One of the issues that plagued the interpretation of these previous studies was the fact that several laboratories, including ours, noted that a certain frequency of rhesus macaques, for reasons still unclear, spontaneously fail to develop anti-SIV-specific immune responses and rapidly progress to AIDS following infection with the uncloned pathogenic SIVmac251 isolate [6,7]. This observation has since been confirmed in macaque monkeys inoculated with the highly pathogenic isolates SIVsmE543, SHIV89.6p or SHIV(DH12R) [5,8,11,16]. In contrast, the current study focused on the role of chronic immune stimulation initiated after the dissemination of SIV, when efficient and established antiviral immune responses had resolved the acute viral replication and the animals had reached their viral load set-points.…”

Derivation and characterization of a highly pathogenic isolate of human immunodeficiency virus type 2 that causes rapid CD4+ cell depletion in Macaca nemestrina

“…The rapid CD4 + cell depletion in HIV-2/287-infected macaques is reminiscent of pathogenic SHIV isolated after adaptation in macaques [19,34,38,49]. An important determinant governing the increased pathogenicity of SHIV after passage in macaques appears to be the en6 gene [25,38]. Enhanced pathogenicity after serial passage of SIVmne or SHIV has been correlated with changes in gag, pol, 6if, and nef genes and the emergence of a neutralization-resistant phenotype [26,27,38,51].…”