Human immunodeficiency virus type l requires interactions with CD4 and coreceptors for infection. The chemokine receptors, CCR5 and CXCR4 are major coreceptors and all HIV-ls use one or both. CCR5-using (R5) viruses are preferentially transmitted. CXCR4-using (X4) viruses can be isolated from up to 50% of AIDS patients. X4 viruses have a broader tropism among T-cells and are associated with a faster depletion of CD4 + T-cells and disease progression. Nevertheless, CD4 depletion and AIDS occur in patients from which only R5 viruses can be isolated. The mechanisms that confer CD4 cell depletion in the absence of X4 viruses are unclear. Our hypothesis is that HIV-1 R5 variants with a broader tropism among CD4 + T-cells emerge late in disease and cause their depletion by direct killing and exacerbating indirect mechanisms of cell death. Preliminary data shows that HIV-1 R5 envelopes confer distinct broad or narrow tropisms for T-cells and macrophages. The broad tropism of R5 envelopes is conferred by capacity to use low levels of CD4 and CCR5 for infection. Envelopes with a narrow/R5 tropism required high CD4 for infection but resisted neutralizing antibodies suggesting that narrow/broad tropism is determined by neutralization potency. Thus neutralization sensitive, broadly tropic R5 viruses may evolve when immunity is declining. Such viruses may also preferentially transmit and predominate in the acute phase and immunoprivileged tissues. We propose to investigate whether HIV-1 with narrow or broad R5 tropisms are associated with particular disease stages. The tropism of HIV-1 envelopes present in semen will also be evaluated. Envelope determinants of narrow/broad tropism will be identified. Finally, we will investigate if different R5 tropisms will impact new therapies that target CCR5. We propose four aims.
Aim 1. Analysis of tropism and receptor requirements of HIV-1 R5 envelopes amplified from different disease stages oj HIV-1 + individuals, from semen and the acute phase of replication.
Aim 2. Identification of the R5 envelope determinants that confer HIV-1 R5 broad, narrow tropisms for T-cells ana macrophages and capacity to exploit low levels of receptors for infection.
Aim 3. Evaluation of the impact of HIV-1 R5 broad and narrow tropism on sensitivity to neutralizing antibodies receptor ligands and envelope interactions with CD4 and CCR5.
Aim 4. Investigation of how HIV-1 R5 virus tropism diversity impacts on sensitivity to CCR5 inhibitors and the evolution of escape mutants.
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