SAMHD1 does it again, now in resting T cells

Abstract

A long-standing question in the HIV field is why HIV-1 fails to replicate in resting CD4(+) T cells. A new study shows that host deoxynucleoside triphosphate triphosphohydrolase (dNTPase) sterile α motif and histidine/aspartic domain-containing protein 1 (SAMHD1), previously shown to block HIV infection in myeloid cells, also restricts HIV replication in resting CD4(+) T cells by hydrolyzing dNTPs, which are needed for reverse transcription of the virus (pages 1682-1687).

Figure 1. SAMHD1 restricts HIV-1 replication in resting CD4⁺ T cells by reducing dNTP concentrations needed for reverse transcription

HIV infection of resting CD4⁺ T cells (left) is blocked by the SAMHD1 restriction factor early in the viral life cycle by limiting the amounts of dNTPs, which are needed to reverse transcribe genomic RNA (black) into a cDNA copy (red). When HIV-1 virions are engineered to contain Vpx (normally present in HIV-2 but not HIV-1) (middle), Vpx orchestrates the proteosomal degradation of SAMHD1, dNTP concentrations rise and reverse transcription, integration of the viral cDNA into the chromosome and transcription of HIV genes occurs. However, an unknown downstream block in these cells interferes with release of virions. In activated CD4+ T cells (right), despite high expression of SAMHD1, dNTP concentrations are elevated enough to support reverse transcription and the viral life cycle goes to completion with release of infectious virus.