Mechanism and pathways controlling HIV-1 viral release

National Institute Of Allergy And Infectious Diseases

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Abstract

In addition to Siglec receptors, we recently began to investigate the potential interaction between C-type lectin receptor, CD62L, and HIV-1 envelope protein gp120. CD4 and chemokine receptors mediate HIV-1 attachment and entry. They are, however, insufficient to explain the preferential viral infection of central memory T cells. We identified L-selectin (CD62L) as a viral adhesion receptor on CD4 T cells. The binding of viral envelope glycans to L-selectin facilitates HIV entry and infection. L-selectin expression on central memory CD4 T cells supports their preferential infection by HIV. Upon infection, the virus downregulates L-selectin expression through shedding, resulting in an apparent loss of central memory CD4+ T cells. Infected effector memory CD4+ T cells, however, remain competent in cytokine production. Surprisingly, inhibition of L-selectin shedding markedly reduces HIV-1 infection and suppresses viral release, suggesting that selectin shedding is required for the viral release. These findings highlight a critical role for cell surface sheddases in HIV-1 release and reveal new antiretroviral strategies based on small molecular inhibitors targeted at metalloproteinases for viral release. Currently utilized antiretroviral therapies are insufficient to eliminate HIV infection and there are no compounds targeting HIV-1 release. We showed that HIV-1 release is not spontaneous, but rather requires caspase-induced phosphatidylserine exchange to facilitate the shedding of the viral adhesion receptor L-selectin/CD62L. All three classes of caspases are activated in HIV infected cells with their activation correlated with the viral infection. Blocking of caspase activation dramatically suppressed HIV-1 infection of primary CD4+ T cells and inhibited the viral release. Budding virions in the presence of a pan-caspase inhibitor become tethered through CD62L, and exhibit reduced structural fitness. Further, HIV accessory gene nef is primarily responsible for inducing caspase activation for viral release. Importantly, caspase inhibition suppressed viral release from patient-derived CD4+ T cells, from both chronically infected individuals and from aviremic viral reservoirs. These results establish a new paradigm with caspase activation critical for the release phase of HIV life-cycle. It suggests a new antiviral strategy targeted at viral reservoir release by suppressing rather than stimulating apoptotic pathways.