Infection and Pathogenicity of Chimeric Simian‐Human Immunodeficiency Viruses in Macaques: Determinants of High Virus Loads and CD4 Cell Killing

Abstract

Chimeric simian-human immunodeficiency viruses (SHIVs) carrying envelope glycoproteins derived from a T cell-macrophage dual-tropic primary isolate (human immunodeficiency virus type 1 [HIV-1] strain DH12) were constructed. When inoculated into macaque monkeys, SHIV(MD14) carrying simian immunodeficiency virus-derived nef established significantly higher virus loads than did SHIV(MD1), which contains the HIV-1 nef gene. Three patterns of CD4 cell depletion were observed in infected monkeys: exponential and irreversible loss to undetectable levels within 10 weeks of infection; marked reduction during acute infection followed by partial recovery and stabilization (lasting from 10 weeks to > 1 year), with a later decline to undetectable levels in some animals; and a transient loss during acute infection. The induced immunodeficiency was accompanied by CD4 cell counts of < 50 cells/microL and was associated with Pneumocystis carinii pneumonia, cytomegalovirus meningoencephalitis, lymphoid depletion, and thymic atrophy.

Apoptosis in SIV infection

“…The risk of developing AIDS-related disease in monkeys infected with SHIV-89.6P variants is strongly influenced by the degree of decline in CD4 þ T lymphocytes during the acute phase of infection. 172,173 Interestingly, infection of macaques with a pathogenic CCR5-specific enveloped virus (SHIV SF162P ) compared with infection with a pathogenic CXCR4-specific enveloped virus (SHIV SF33A.2 ) demonstrated that despite comparable levels of viral replication, animals have distinct pathogenic outcomes. R5-tropic SHIV causes a dramatic loss of CD4 þ intestinal T cells and a gradual depletion in peripheral CD4 þ T cells, while infection with X4-tropic SHIV causes a profound loss in peripheral T cells that was not paralleled in the intestine.…”

Protective Efficacy of an AIDS Vaccine, a Single DNA Priming Followed by a Single Booster with a Recombinant Replication-Defective Sendai Virus Vector, in a Macaque AIDS Model

“…The DNA used for the priming (referred to as CMV-SHIVdEN) was constructed from an env and nef deletion SHIV DNA (SIVGP1 DNA) (17,24) by replacing the 5Ј long terminal repeat region with a cytomegalovirus promoter with an immediate-early enhancer and the 3Ј long terminal repeat region with simian virus 40 poly(A). At DNA vaccination, the animals received 5 mg of CMV-SHIVdEN DNA intramuscularly.…”

Induction of Disease by a Molecularly Cloned Highly Pathogenic Simian Immunodeficiency Virus/Human Immunodeficiency Virus Chimera Is Multigenic

“…Complete nucleotide sequencing of SHIV DH12R-CL-7 revealed that 42 amino acid changes, relative to the starting sequence of nonpathogenic SHIV DH12 (previously designated SHIV MD14YE [20]), had accompanied the acquisition of the highly pathogenic phenotype (Fig. 3, top).…”

“…This disease phenotype has been previously reported for three independently derived uncloned SHIVs (11,14,17) and is applicable to only one of the three full-length infectious SHIV DH12R clones obtained in this study. The acquisition of these unusual pathogenic characteristics appears to be multigenic: 42 amino acid substitutions, relative to the starting nonpathogenic SHIV DH12 clone (20), distributed among several viral genes, were present in SHIV DH12R-CL-7 . In contrast to studies of the envelope glycoproteins associated with molecularly cloned SHIV KB9 and SHIV HXBc2P-3.2 , which were reported to be the principal determinants inducing CD4 ϩ T-lymphocyte depletion (4,15), the entire env gene of SHIV DH12R-CL-7 , by itself, failed to confer the rapid and irreversible CD4 ϩ T-cell-depleting properties following its insertion into the genome of nonpathogenic parental strain SHIV DH12 .…”

“…as previously described (22). Positive recombinant phage plaques, identified by using the 8.1-kbp HaeII-XhoI fragment (encompassing the gag through the env sequences) from SHIV DH12 (20) as a probe, were expanded, and the insert was transferred to pBR322. Two long terminal repeat linear forms of SHIV DNA were reconstituted from SalI-EcoRI and EcoRI-NarI subfragments of each clone as previously described (16,22).…”