APOBEC3H haplotypes and HIV-1 pro-viral vif DNA sequence diversity in early untreated human immunodeficiency virus–1 infection

112

The APOBEC3 family comprises seven cytidine deaminases (APOBEC3A [A3A] to A3H), which are expressed to various degrees in HIV-1 susceptible cells. The HIV-1 Vif protein counteracts APOBEC3 restriction by mediating its degradation by the proteasome. We hypothesized that Vif proteins from various HIV-1 subtypes differ in their abilities to counteract different APOBEC3 proteins. Seventeen Vif alleles from seven HIV-1 subtypes were tested for their abilities to degrade and counteract A3G, A3F, and A3H haplotype II (hapII). We show that most Vif alleles neutralize A3G and A3F efficiently but display differences with respect to the inhibition of A3H hapII. The majority of non-subtype B Vif alleles tested presented some activity against A3H hapII, with two subtype F Vif variants being highly effective in counteracting A3H hapII. The residues required for activity were mapped to two residues in the amino-terminal region of Vif (positions 39F and 48H). Coimmunoprecipitations showed that these two amino acids were necessary for association of Vif with A3H hapII. These findings suggest that the A3H hapII binding site in Vif is distinct from the regions important for A3G and A3F recognition and that it requires specific amino acids at positions 39 and 48. The differential Vif activity spectra, especially against A3H hapII, suggest adaptation to APOBEC3 repertoires representative of different human ancestries. Phenotypic assessment of anti-APOBEC3 activity of Vif variants against several cytidine deaminases will help reveal the requirement for successful replication in vivo and ultimately point to interventions targeting the Vif-APOBEC3 interface.

Section: Discussionmentioning

confidence: 99%

“…Moreover, A3H has several haplotypes, some of which are highly active against HIV-1 (haplotypes II, V, and VII) (5,9,18,19,29,43,52). Interestingly, the allele frequency of the active A3H hapII differs considerably among human ethnicities, being high in African and low in European and Asian populations (29,43).…”

mentioning

confidence: 99%

The Activity Spectrum of Vif from Multiple HIV-1 Subtypes against APOBEC3G, APOBEC3F, and APOBEC3H

Binka

Ooms

Steward

et al. 2012

112

“…APOBEC3H haplotype I (A3H HapI), the major haplotype in Caucasians, has low steady-state protein expression levels due to instability and consequently does not exhibit significant antiviral activity (7,10,13,23). However, A3H HapII, which is more prevalent in people of African descent, expresses a stable protein and has been reported to exhibit antiviral activity (24).…”

mentioning

confidence: 99%

APOBEC3G Restricts HIV-1 to a Greater Extent than APOBEC3F and APOBEC3DE in Human Primary CD4 ⁺ T Cells and Macrophages

Chaipan

Smith

et al. 2013

102

116

؉ T cells and macrophages, and only the NL4-3 YRHHY>A5 mutant showed a 2-to 4-day delay in replication compared to the wild type. During the subsequent 27 days (round 2) of cultures initiated with peak virus obtained from round 1, the NL4-3 YRHHY>A5 mutant exhibited a longer, 8-to 10-day delay and the NL4-3 DRMR>A4 mutant exhibited a 2-to 6-day delay in replication compared to the wild type. The NL4-3 YRHHY>A5 and NL4-3 DRMR>A4 mutant proviruses displayed G-to-A hypermutations primarily in GG and GA dinucleotides as expected of A3G-and A3F-or A3DE-mediated deamination, respectively. We conclude that A3G exerts a greater restriction effect on HIV-1 than A3F and A3DE.

“…Moreover, a recent study suggested that the most active haplotype of APOBEC3H is associated with reduced viral load in early, untreated HIV-infected individuals (7). Hence, the APOBEC3H genotype of HIV-infected individuals may have an impact on the evolution of their viruses, which suggests an important in vivo role for APOBEC3H polymorphisms in HIV infection.…”

mentioning

confidence: 99%

Polymorphism in Human APOBEC3H Affects a Phenotype Dominant for Subcellular Localization and Antiviral Activity

Emerman

2011

100

The APOBEC3 family of cytidine deaminases is part of the innate host defense targeted toward retroviruses and retroelements. APOBEC3H is the most distantly related member of the family and carries functional polymorphisms in current human populations. Haplotype II of APOBEC3H, which is more commonly found in individuals of African descent, encodes a protein with the highest antiviral activity in cells, whereas the other haplotypes encode proteins with weak or no antiviral activity. Here, we show that the different human APOBEC3H haplotypes exhibit differential subcellular localizations, as the haplotype I protein is mostly found in the nucleus and the haplotype II protein is mostly localized to the cytoplasm. The determinant responsible for this phenotype maps to a single amino acid that is also important for APOBEC3H protein stability. Furthermore, we show that the cytoplasmic localization is dominant over nuclear localization, by using fusion proteins of APOBEC3H. Our data support a model in which the APOBEC3H protein encoded by haplotype II is actively retained in the cytoplasm by interacting with specific host factors, whereas the less active protein encoded by haplotype I is allowed to enter the nucleus by a passive mechanism. Together, cytoplasmic localization and its link with protein stability correlate with the ability of APOBEC3H to inhibit HIV replication, providing a mechanistic basis for the differential antiviral activities of different APOBEC3H haplotypes.