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

Abstract

SummaryCD4 ϩ T lymphocyte depletion in human immunodeficiency virus type 1 (HIV-1)-infected humans underlies the development of acquired immune deficiency syndrome. Using a model in which rhesus macaques were infected with chimeric simian-human immunodeficiency viruses (SHIVs), we show that both the level of viremia and the structure of the HIV-1 envelope glycoprotein ectodomains individually contributed to the efficiency with which CD4 ϩ T lymphocytes were depleted. The envelope glycoproteins of recombinant SHIVs that efficiently caused loss of CD4 ϩ T lymphocytes exhibited increased chemokine receptor binding and membrane-fusing capacity compared with those of less pathogenic viruses. These studies identify the HIV-1 envelope glycoprotein ectodomains as determinants of CD4 ϩ T lymphocyte loss in vivo and provide a foundation for studying pathogenic mechanisms.

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

“…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 . Similarly, substitution of gag-pol sequences from pathogenic SIV E543 could not replace analogous SIV mac239 genes in SHIV DH12R-CL-7 .…”

“…Although these changes were distributed throughout the viral genome, they primarily affected the env and nef genes. On the basis of increased chemokine receptor binding affinity, membrane fusion capacity, and/or neutralization resistance, earlier analyses of the molecularly cloned SHIV KB9 derivative of SHIV 89.6P (15) and the molecularly cloned SHIV HXBc2P-3.2 derivative of SHIV KU-1 (4) concluded that FIG. 3.…”

“…The mechanism(s) underlying the rapid elimination of CD4 ϩ T lymphocytes and induction of immunodeficiency by pathogenic SHIVs remains unknown, although the increased fusogenicity of the envelope glycoprotein and the infection of a substantial fraction of CD4 ϩ T cells in lymphoid tissue during the first weeks postinoculation have been proposed to explain the unusual disease phenotype (4,10,15). Because the fraction of CD4 ϩ T cells in blood and lymphoid tissues expressing CXCR4 is very large (Ͼ80%) (23, 25) (Y. Nishimura and M. Martin, unpublished data), complete and systemic elimination of this T-lymphocyte subset by X4-tropic SHIV DH12R-CL-7 could simply reflect the targeting and unrelenting depletion of these cells.…”

Germinal Center Function in the Spleen during Simian HIV Infection in Rhesus Monkeys

“…Subject Mm18284 was infected with SHIV-KB9ct, and subject Mm19941 was infected with SHIV-KB9(Ϫ305). Some immunologic and virologic data from these monkeys have been previously reported (42,45,47). Infection of both animals was confirmed by serologic and virologic assays (45,47).…”

“…SHIV-KB9ct and SHIV-KB9(Ϫ305) are hybrid viruses that combine aspects of the parental Ϫ89.6 and more pathogenic ϪKB9 clones. These viruses were selected for the present study because they expressed a gp120 identical with or cross-reactive with that of the rgp120-89.6 used as an inverse immunohistochemical probe and show increased pathogenicity compared with the parental SHIV-89.6 (45,47).…”