Heat-Stable Molecule Derived from Streptococcus cristatus Induces APOBEC3 Expression and Inhibits HIV-1 Replication

Dhiver

et al. 2020

Sci Rep

Strategies to cure HIV-infected patients by virus-targeting drugs have failed to date. We identified a HIV-1-seropositive woman who spontaneously suppressed HIV replication and had normal CD4-cell counts, no HIV-disease, no replication-competent virus and no cell HIV DNA detected with a routine assay. We suspected that dramatic HiV DnA degradation occurred post-infection. We performed multiple nested-PCRs followed by Sanger sequencing and applied a multiplex-PCR approach. Furthermore, we implemented a new technique based on two hybridization steps on beads prior to next-generation sequencing that removed human DNA then retrieved integrated HIV sequences with HIV-specific probes. We assembled ≈45% of the HIV genome and further analyzed the G-to-A mutations putatively generated by cellular APOBEC3 enzymes that can change tryptophan codons into stop codons. We found more G-to-A mutations in the HiV DnA from the woman than in that of her transmitting partner. Moreover, 74% of the tryptophan codons were changed to stop codons (25%) or were deleted as a possible consequence of gene inactivation. Finally, we found that this woman's cells remained HiV-susceptible in vitro. Our findings show that she does not exhibit innate HIV-resistance but may have been cured of it by extrinsic factors, a plausible candidate for which is the gut microbiota.

Section: Discussionmentioning

confidence: 99%

Section: Apobec3 Gene Sequencing and Expression Level Assessment Apomentioning

confidence: 99%

RETRACTED ARTICLE: Dramatic HIV DNA degradation associated with spontaneous HIV suppression and disease-free outcome in a young seropositive woman following her infection

Dhiver

et al. 2020

Sci Rep

“…Otherwise, APOBEC3G activity may have been temporarily boosted by interferon-alpha administered to the index case for his chronic hepatitis C 24 , 27 . In addition, a recent study suggests that co-infection with Streptococcus may enhance the activity of these proteins and inhibit HIV growth by generating hypermutability 28 . The Vif protein theoretically blocks APOBEC3G activity 29 .…”

Section: Discussionmentioning

confidence: 99%

HIV infection en route to endogenization: two cases

Ravaux

Clinical Microbiology and Infection

et al. 2014

The long-term spontaneous evolution of humans and the human immunodeficiency virus (HIV) is not well characterized; many vertebrate species, including humans, exhibit remnants of other retroviruses in their genomes that question such possible endogenization of HIV. We investigated two HIV-infected patients with no HIV-related disease and no detection with routine tests of plasma HIV RNA or cell-associated HIV DNA. We used Sanger and deep sequencing to retrieve HIV DNA sequences integrated in the human genome and tested the host humoral and cellular immune responses. We noticed that viruses from both patients were inactivated by the high prevalence of the transformation of tryptophan codons into stop codons (25% overall (3–100% per gene) and 24% overall (0–50% per gene)). In contrast, the humoral and/or cellular responses were strong for one patient and moderate for the other, indicating that a productive infection occurred at one stage of the infection. We speculate that the stimulation of APOBEC, the enzyme group that exchanges G for A in viral nucleic acids and is usually inhibited by the HIV protein Vif, has been amplified and made effective from the initial stage of the infection. Furthermore, we propose that a cure for HIV may occur through HIV endogenization in humans, as observed for many other retroviruses in mammals, rather than clearance of all traces of HIV from human cells, which defines viral eradication.

“…We postulate that APOBEC3G could play a role in the inactivation of endogenized retroviruses. Moreover, the efficacy of APOBEC3G could be increased by events such as mutations at critical positions of the Vif-encoding gene, as demonstrated in previous studies [14,26], or coinfection with Streptococcus, which enhances the activity of this protein and inhibits HIV growth by generating hypermutability [63]. Second, on the basis of previous observations, it is conceivable that a fraction of HIV DNA may not integrate through the conventional mechanism mediated by HIV integrase and involving HIV long terminal repeats.…”

Section: Innate Immunitymentioning

confidence: 87%

Reevaluation of possible outcomes of infections with human immunodeficiency virus

Clinical Microbiology and Infection

Decroly

et al. 2016

Several lines of evidence indicate that HIV infection can result in several possible incomes, including a very small proportion of individuals whose HIV replication is controlled after treatment interruption (known as HIV posttreatment controllers) or spontaneously without any treatment (known as HIV elite controllers). Both types of individuals are HIV RNA negative but HIV DNA positive, with living virus which can be stimulated ex vivo. A review was conducted to assess the literature on yet rarer cases with detectable integrated HIV DNA without HIV infectious virus in HIV-seropositive or -negative individuals. Three categories of patients were identified: (a) HIV-seropositive individuals with apparent spontaneous cure from their HIV infection, (b) HIV-seronegative children born to HIV-infected mothers and (c) highly exposed seronegative adults. Validity criteria were proposed to assess the presence of integrated HIV DNA as possible or unquestionable in these three categories. Only three articles among the 22 ultimately selected fulfilled these criteria. Among the highly exposed seronegative subjects, some individuals were described as being without integrated HIV DNA, probably because these subjects were not investigated using relevant, highly sensitive methods. Finally, we propose a definition of spontaneous cure of HIV infection based on clinical, immunologic and virologic criteria.