The genes of HIV-1, the virus that causes AIDS, are encoded in a single strand of RNA. When HIV-1 infects human CD4+ T cells, the virus must first undergo reverse transcription—conversion of its single-stranded RNA genome into double-stranded DNA. The viral DNA integrates into the host’s cell’s nucleus, so that the host cell’s DNA genome will replicate HIV-1 into many new single-stranded RNA copies.

Scientists have assumed that the host cell’s cytoplasm is the site for reverse transcription and for uncoating—another early step in HIV-1 replication in which the virus sheds its protective capsule after entering the T cell. In a study published online on September 29 in Cell Reports, Felipe Diaz-Griffero, Ph.D., and colleagues show that both of those early HIV-1 replication steps actually take place in the host cell’s nucleus rather than the cytoplasm.

This finding indicates that HIV-1 must enter the host cell’s nucleus before reverse transcription and uncoating occur—which fundamentally changes our understanding of HIV-1 infection.

It now appears that the important steps in HIV-1 replication—reverse transcription, uncoating, and integration into host cell’s genome—all occur in the nucleus. The findings also link HIV-1 replication with HIV-1 “reservoirs”—scells containing latent HIV-1 that become established early in the infection process. The presence of latent HIV-1 reservoirs, which can later reactivate and renew infection, has so far thwarted efforts to develop functional cures for AIDS.

Knowing precisely where HIV-1 replicates in human T cells can help in developing more efficient inhibitors of HIV-1 infection and could help lead to treatment strategies for preventing HIV-1 reservoirs from forming.

Dr. Diaz-Griffero is professor of microbiology & immunology and Elsie Wachtel Faculty Scholar at Einstein.