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Coreceptor phenotype of natural human immunodeficiency virus with nef deleted evolves in vivo, leading to increased virulence.

ABSTRACT: The Sydney Blood Bank Cohort is a group of patients with slowly progressive infection by a human immunodeficiency virus strain containing spontaneous deletions within the nef long terminal repeat region. In 1999, 18 years after the initial infection, one of the members (D36) developed AIDS. In this work, we used an ex vivo human lymphoid cell culture system to analyze two viral isolates obtained from this patient, one prior to the onset of AIDS in 1995 and one after disease progression in 1999. Both D36 isolates were less potent in depleting CD4(+) T cells than a reference dualtropic, nef-bearing viral isolate. However, the 1999 isolate was measurably more cytotoxic to CD4(+) T cells than the 1995 isolate. Interestingly, although both isolates were nearly equally potent in depleting CCR5(+) CD4(+) T cells, the cytotoxic effect of the 1999 isolate toward CCR5(-) CD4(+) T cells was significantly higher. Furthermore, GHOST cell infection assays and blocking experiments with the CXCR4 inhibitor AMD3100 showed that the later D36 1999 isolate could infect both CCR5(+) and CCR5(-) CXCR4(+) cells efficiently, while infection by the 1995 isolate was nearly completely restricted to CCR5(+) cells. Sequence analysis of the V1/V2 and V3 regions of the viral envelope protein gp120 revealed that the more efficient CXCR4 usage of the later isolate might be caused by an additional potential N-glycosylation site in the V1/V2 loop. In conclusion, these data show that an in vivo evolution of the tropism of this nef-deleted strain toward an X4 phenotype was associated with a higher cytopathic potential and progression to AIDS.

SUBMITTER: Jekle A

PROVIDER: S-EPMC136331 | biostudies-literature | 2002 Jul

REPOSITORIES: biostudies-literature

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Coreceptor phenotype of natural human immunodeficiency virus with nef deleted evolves in vivo, leading to increased virulence.

Jekle Andreas A Schramm Birgit B Jayakumar Prerana P Trautner Verena V Schols Dominique D De Clercq Erik E Mills John J Crowe Suzanne M SM Goldsmith Mark A MA

Journal of virology 20020701 14

The Sydney Blood Bank Cohort is a group of patients with slowly progressive infection by a human immunodeficiency virus strain containing spontaneous deletions within the nef long terminal repeat region. In 1999, 18 years after the initial infection, one of the members (D36) developed AIDS. In this work, we used an ex vivo human lymphoid cell culture system to analyze two viral isolates obtained from this patient, one prior to the onset of AIDS in 1995 and one after disease progression in 1999. ...[more]

PMID: 12072497

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Project description:While simian immunodeficiency viruses (SIVs) are generally nonpathogenic in their natural hosts, dramatic increases in pathogenicity may occur upon cross-species transmission to new hosts. Deciphering the drivers of these increases in virulence is of major interest for understanding the emergence of new human immunodeficiency viruses (HIVs). We transmitted SIVsab from the sabaeus species of African green monkeys (AGMs) to pigtailed macaques (PTMs). High acute viral replication occurred in all SIVsab-infected PTMs, yet the outcome of chronic infection was highly variable, ranging from rapid progression to controlled infection, which was independent of the dynamics of acute viral replication, CD4(+) T cell depletion, or preinfection levels of microbial translocation. Infection of seven PTMs with plasma collected at necropsy from a rapid-progressor PTM was consistently highly pathogenic, with high acute and chronic viral replication, massive depletion of memory CD4(+) T cells, and disease progression in all PTMs. The plasma inoculum used for the serial passage did not contain adventitious bacterial or viral contaminants. Single-genome amplification showed that this inoculum was significantly more homogenous than the inoculum directly derived from AGMs, pointing to a strain selection in PTMs. In spite of similar peak plasma viral loads between the monkeys in the two passages, immune activation/inflammation levels dramatically increased in PTMs infected with the passaged virus. These results suggest that strain selection and a massive cytokine storm are major factors behind increased pathogenicity of SIV upon serial passage and adaptation of SIVs to new hosts following cross-species transmission.We report here that upon cross-species transmission and serial passage of SIVsab from its natural host, the sabaeus African green monkey (AGM), to a new host, the pigtailed macaque (PTM), viral adaptation and increased pathogenicity involve strain selection and a massive cytokine storm. These results permit the design of strategies aimed at preventing cross-species transmission from natural hosts of SIVs to humans in areas of endemicity. Furthermore, our study describes a new animal model for SIV infection. As the outcomes of SIVsab infection in PTMs, African green monkeys, and rhesus macaques are different, the use of these systems enables comparative studies between pathogenic, nonpathogenic, and elite-controlled infections, to gain insight into the mechanisms of SIV immunodeficiency and comorbidities.

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Coreceptor phenotype of natural human immunodeficiency virus with nef deleted evolves in vivo, leading to increased virulence.

Publications

Coreceptor phenotype of natural human immunodeficiency virus with nef deleted evolves in vivo, leading to increased virulence.

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