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Review
. 2020 Apr 21;12(4):471.
doi: 10.3390/v12040471.

Role of Divalent Cations in HIV-1 Replication and Pathogenicity

Nabab Khan  1 , Xuesong Chen  1 , Jonathan D Geiger  1
Affiliations
Review

Role of Divalent Cations in HIV-1 Replication and Pathogenicity

Nabab Khan et al. Viruses. .

Abstract

Divalent cations are essential for life and are fundamentally important coordinators of cellular metabolism, cell growth, host-pathogen interactions, and cell death. Specifically, for human immunodeficiency virus type-1 (HIV-1), divalent cations are required for interactions between viral and host factors that govern HIV-1 replication and pathogenicity. Homeostatic regulation of divalent cations' levels and actions appear to change as HIV-1 infection progresses and as changes occur between HIV-1 and the host. In people living with HIV-1, dietary supplementation with divalent cations may increase HIV-1 replication, whereas cation chelation may suppress HIV-1 replication and decrease disease progression. Here, we review literature on the roles of zinc (Zn2+), iron (Fe2+), manganese (Mn2+), magnesium (Mg2+), selenium (Se2+), and copper (Cu2+) in HIV-1 replication and pathogenicity, as well as evidence that divalent cation levels and actions may be targeted therapeutically in people living with HIV-1.

Keywords: HIV-1 associated neurocognitive disorders; divalent cations; endolysosomes; human immunodeficiency virus type-1; transactivator of transcription.

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Conflict of interest statement

The authors disclose that this manuscript was written without any commercial or financial associations that could be construed as a conflict of interest.

Figures

Figure 1
Figure 1
Roles of divalent cations in the HIV-1 life cycle and pathogenicity: 1. HIV-1 infects cells by first binding gp120 with CD4 receptors and CXCR4/CCR5 co-receptors. Post endocytosis, HIV-1 escapes from endolysosomes (EL) into the cytosol, where it is uncoated. 2. Viral RNA is reverse-transcribed into viral DNA. During reverse transcription, Mn2+, Mg2+, and Zn2+ control reverse transcription by regulating RNAse H and RT enzymes. Prior to integration, non-integrated DNA transcribes synthesis of early proteins Tat, Rev, and Nef. 3. IN requires divalent cations, including Mn2+/Mg2+ and Zn2+, for proper integration into the host genome. 4. Post integration, Tat elongates and terminates the transcription process of HIV-1. Zinc enhances interactions between Tat and the host factors (CycT1 and CDK9) with the HIV-1 LTR promoter for proper transcription. 5. Post transcription, HIV-1 transcripts (viral mRNAs) are transported to the cytosol by the Rev protein with the help of eIF5α. To be functional, eIF5α needs iron. After translation, HIV-1 is transported to the cell membrane, where it assembles progeny virion particles. 6. During virus assembly, the virus needs a cellular protein, ABCE1 (ATP-binding cassette sub-family E member 1), for proper assembly by enhancing accessibility of the HIV-1 Gag protein to the virus packaging site. However, the NCp protein is also important for virus assembly to arrange the Gag protein in virion particles. Indeed, zinc is required for Gag dimerization and trafficking to the cell membrane. However, levels of divalent cations are altered in HIV-1 infection and are differentially regulated as HIV-1 disease progresses. Supplementation of divalent cations may either be beneficial or harmful to the virus, and extracellular FAC can inhibit HIV-1 escape from endolysosomes. Abbreviations: CD4: cluster differentiation 4, CXCR4: Cysteine-X-Cysteine chemokine receptor type 4, CCR5: Cysteine-Cysteine chemokine receptor type 5, Gp120: glycoprotein 120, EL: endolysosome, FAC: ferric ammonium citrate, vRNA: viral RNA, RNAse H: ribonuclease H, RT: reverse transcriptase, vcDNA: viral complementary DNA, PIC: pre-integration complex, Nef: Negative regulatory factor, IN: Integrase, CDK9: cyclin-dependent kinase 9, LTR: long terminal repeat, Tat: transactivator of transcription, vmRNAs: viral messenger RNAs, Rev: regulator of expression of virion particles, eIF5α: translation initiation factor 5α, and NCp: nucleocapsid protein.
Figure 2
Figure 2
Roles of divalent cations in HIV-1 Tat-mediated pathogenicity. Extracellular Tat is a neurotoxin implicated in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). Tat enters bystander cells by receptor-mediated endocytosis. Internalized Tat disturbs endolysosome functions, including de-acidification. When de-acidified, Tat is released from endolysosomes and enters the nucleus where it activates HIV-1 LTR transactivation. Endolysosomes contain divalent cations and these can induce Tat oligomerization. Because Tat oxidizes rapidly, Tat can be oxidized by iron-induced reactive oxygen species (ROS). Disturbed iron homeostasis may be involved in increasing levels of various neurotoxic substances, including β-amyloid, p-Tau, and α-synuclein.
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