The Impact of Macrophage Nucleotide Pools on HIV-1 Reverse Transcription, Viral Replication, and the Development of Novel Antiviral Agents

Abstract

Macrophages are ubiquitous and represent a significant viral reservoir for HIV-1. Macrophages are nondividing, terminally differentiated cells, which have a unique cellular microenvironment relative to actively dividing T lymphocytes, all of which can impact HIV-1 infection/replication, design of inhibitors targeting viral replication in these cells, emergence of mutations within the HIV-1 genome, and disease progression. Scarce dNTPs drive rNTP incorporation into the proviral DNA in macrophages but not lymphocytes. Furthermore, the efficacy of a ribose-based inhibitor that potently inhibits HIV-1 replication in macrophages, has prompted a reconsideration of the previously accepted dogma that 2'-deoxy-based inhibitors demonstrate effective inhibition of HIV-1 replication. Additionally, higher levels of dUTP and rNTP incorporation in macrophages, and lack of repair mechanisms relative to lymphocytes, provide a further mechanistic understanding required to develop targeted inhibition of viral replication in macrophages. Together, the concentrations of dNTPs and rNTPs within macrophages comprise a distinctive cellular environment that directly impacts HIV-1 replication in macrophages and provides unique insight into novel therapeutic mechanisms that could be exploited to eliminate virus from these cells.

Figure 1

SAMHD1 (SAM domain and HD domain-containing protein 1) and its regulatory mechanism of dNTPs as a host restriction mechanism to prevent HIV-1 infection in macrophages/macrophage-like cells. SAMHD1 cleaves dNTPs into a nucleoside and a triphosphate, rendering levels of intact dNTPs suboptimal to facilitate HIV-1 RT mediated DNA synthesis (a), but low SAMHD1 expression in lymphocytes prevents SAMHD1-mediated restriction in dividing cells such as activated CD4 T cells (b) [20].

Figure 2

Potential impact of levels/ratios of dNTP : rNTP in macrophages upon emergence of mutagenic HIV-1. Similar ratios of dNTP : rNTP (point 1) confer preferential incorporation of rNTP and rNMP into the growing viral DNA strand (point 2). Together, with suboptimal levels of repair machinery found in macrophages, these incorporations are a known correlate for production of mutagenic HIV-1 (point 3).