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Review
. 2022 Jul 26;14(8):1622.
doi: 10.3390/v14081622.

Mechanistic Interplay between HIV-1 Reverse Transcriptase Enzyme Kinetics and Host SAMHD1 Protein: Viral Myeloid-Cell Tropism and Genomic Mutagenesis

Nicole E Bowen  1 , Adrian Oo  1 , Baek Kim  1   2
Affiliations
Review

Mechanistic Interplay between HIV-1 Reverse Transcriptase Enzyme Kinetics and Host SAMHD1 Protein: Viral Myeloid-Cell Tropism and Genomic Mutagenesis

Nicole E Bowen et al. Viruses. .

Abstract

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has been the primary interest among studies on antiviral discovery, viral replication kinetics, drug resistance, and viral evolution. Following infection and entry into target cells, the HIV-1 core disassembles, and the viral RT concomitantly converts the viral RNA into double-stranded proviral DNA, which is integrated into the host genome. The successful completion of the viral life cycle highly depends on the enzymatic DNA polymerase activity of RT. Furthermore, HIV-1 RT has long been known as an error-prone DNA polymerase due to its lack of proofreading exonuclease properties. Indeed, the low fidelity of HIV-1 RT has been considered as one of the key factors in the uniquely high rate of mutagenesis of HIV-1, which leads to efficient viral escape from immune and therapeutic antiviral selective pressures. Interestingly, a series of studies on the replication kinetics of HIV-1 in non-dividing myeloid cells and myeloid specific host restriction factor, SAM domain, and HD domain-containing protein, SAMHD1, suggest that the myeloid cell tropism and high rate of mutagenesis of HIV-1 are mechanistically connected. Here, we review not only HIV-1 RT as a key antiviral target, but also potential evolutionary and mechanistic crosstalk among the unique enzymatic features of HIV-1 RT, the replication kinetics of HIV-1, cell tropism, viral genetic mutation, and host SAMHD1 protein.

Keywords: SAMHD1; antiretroviral therapy; cell tropism; drug resistance; human immunodeficiency virus type 1; mutation; retrovirus; reverse transcriptase.

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Conflict of interest statement

The authors declare no conflict of interest, and the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Schematic representation of HIV-1 RT structure. HIV-1 RT consists of two subunits, p66 and p51. The p66 subunit harbors both DNA polymerase (blue segment) and RNase H (green segment) domains, whereas p51, which is a proteolytic cleavage product of p66 subunit, does not have an active RNase H domain (residue 427–440). HIV-1 RT DNA polymerase domain, which captures DNA primer annealed to RNA or DNA template, in the form of a clasping right hand, can be further classified into the finger, palm, and thumb subdomains, whereas the connection subdomain links polymerase and RNase H domains. Amino-acid residues crucial for the enzymatic catalytic sites of DNA polymerase and RNase H activities are marked with respective colors.
Figure 2
Figure 2
Structural representation of SAMHD1 regulation. The active SAMHD1 tetramer forms when each allosteric site is filled with nucleotides, shown above as dGTP (gray). This allows for the active site to bind deoxynucleotides for hydrolysis, shown above as dGTP (pink). SAMHD1 hydrolysis activity is regulated by several post-translational modifications: phosphorylation at T592 (brown), acetylation at K405 (blue), SUMOylation at K595 (green), and oxidation of C341 (teal), C350 (red), and C522 (yellow). Regulatory residues are shown for only one chain for model simplification. PBD structure 4BZB [93] and VMD software were used for modeling.
Figure 3
Figure 3
Model of mechanistic interplay among cellular dNTP levels, SAMHD1, RT enzyme kinetics, cell tropism, and genomic mutagenesis of HIV-1. In non-dividing cells, such as macrophages, dNTP pool is typically low as a result of the dNTPase activity of SAMHD1. Lentiviruses harboring Vpx, such as HIV-2, and several SIV strains counteract this antiviral restriction effect of SAMHD1 by proteasomally degrading SAMHD1 and elevating cellular dNTP levels, which promotes viral reverse-transcription kinetics in macrophages. By contrast, HIV-1 bypasses the low-dNTP pool of macrophages (dashed blue lines) via the unique kinetic properties of RT (low Kd and Km values), which facilitate viral reverse transcription within this limited-dNTP cellular environment. This mechanistically contributes towards the myeloid-cell tropism of HIV-1. Concomitantly, this uniquely efficient dNTP incorporation efficiency of HIV-1 RT can also promote the high efficiency of HIV-1 RT in mismatched-primer extension, which can increase viral mutagenesis, suggesting that myeloid cell tropism and high genomic variability of HIV-1 are mechanistically connected (dashed purple lines).
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