Structural mechanism of CD4-independent HIV infection

Tuesday, October 25, 2011 — Poster Session II
Noon – 2:00 p.m.	Natcher Conference Center	NCI	STRUCTBIO-10

* FARE Award Winner

Authors

• T White
• R Nandwani
• A Nath
• S Subramaniam

Abstract

Upon HIV-1 disease progression, immune responses are repressed due to CD4+ T-cell depletion. With immune system repression, variant HIV viruses can emerge. One such virus has relaxed cell entry requirements that no longer require CD4 for cell entry (CD4-independence). In the brain, non-CD4+ cells are infected; this correlates with AIDS-induced encephalopathy and dementia. We have now demonstrated using cryo-electron tomography that both CD4-independent SIV obtained by cell passage displays a similar open conformation previously observed upon viral entry. Previously protected, conserved gp120 regions are now exposed in the open conformation, available as epitopes to elicit antibodies—a necessity for a successful AIDS vaccine. We are now exploring the possibility that the occurrence of a constitutively open state may be ubiquitous to other CD4-independent viruses isolated from productive viral infection. Preliminary investigations using cryo-ET are already under way to test this hypothesis using a number of matched pairs of CD4-dependent and independent SIV and HIV-1 variants. Administration of immunogens that mimic the open state of trimeric Env could potentially result in elicitation of novel broadly neutralizing antibodies reactive to both CD4-dependent and CD4-independent HIV strains.

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