Restrictions to HIV-1 replication in resting CD4+ T lymphocytes

Abstract

CD4+ T lymphocytes represent the main target cell population of human immunodeficiency virus (HIV). In an activated state, CD4+ T cells residing in lymphoid organs are a major reservoir of ongoing HIV-1 replication in infected individuals. In contrast, resting CD4+ T cells are highly resistant to productive HIV-1 infection, yet are massively depleted during disease progression and represent a substantial latent reservoir for the virus in vivo. Barriers preventing replication of HIV-1 in resting CD4+ T cells include a rigid layer of cortical actin and, early after HIV-1 entry, a block that limits reverse transcription of incoming viral RNA genomes. Defining the molecular bases of these restrictions has remained one of the central open questions in HIV research. Recent advances unraveled mechanisms by which HIV-1 bypasses the entry block and established the host cell restriction factor SAMHD1, a deoxynucleoside triphosphate triphosphohydrolase, as a central determinant of the cellular restriction to HIV-1 reverse transcription in resting CD4+ T cells. This review summarizes our current molecular and pathophysiological understanding of the multi-faceted interactions of HIV-1 with resting CD4+ T lymphocytes.

Structural Basis of Allosteric Activation of Sterile α Motif and Histidine-Aspartate Domain-containing Protein 1 (SAMHD1) by Nucleoside Triphosphates

“…It plays an important role in innate immunity, targeting retroviral infection by limiting the cellular dNTP pools, essential for reverse transcription (42)(43)(44)(45). Here we elucidated the structural basis for the broad activity toward different dNTP substrates through a series of different enzyme-dNTP/NTP crystal structures (i.e.…”

Impaired IL-2 expression in latent HIV-1 infection

“…In general, HIV-1 replication tightly couples with the activation of these target cells because the HIV-1 promoter long terminal repeat (LTR) includes NFAT and NF-kB, which are sensitively activated by T cell activation [10,11]. Therefore, HIV readily undergoes replication in activated memory CD4þ T cells but not in resting T cells [11].…”

SAMHD1 Restricts Herpes Simplex Virus 1 in Macrophages by Limiting DNA Replication

“…The SAMHD1 enzyme restricts retrovirus infection in macrophages, dendritic cells, and resting CD4 ϩ T cells (28)(29)(30). It was identified through biochemical purification of the accessory factor Vpx encoded by certain lentiviruses (8,9).…”