Endogenous retroviruses, or ERVs, are the fossilized remnants of retroviruses that once infected the germ-line cells of ancestral hosts. When a retrovirus inserts its provirus into the DNA of a sperm or egg cell that goes on to contribute to the next generation, the insertion can be inherited vertically, copying itself into every cell of every descendant. Over millions of years these elements accumulate mutations, deletions and recombination events, but their diagnostic architecture, including long terminal repeats flanking the core retroviral genes gag, pol and env, often remains recognizable. Because integration events are effectively permanent and their ages can be estimated, ERVs function as paleontological records of the viruses that circulated in host populations deep in evolutionary time.

To recover these viral fossils from the macaque genome, the researchers employed a homology-based, genome-wide screen designed to detect relatively intact proviruses rather than the far more numerous degraded fragments and solo long terminal repeats that litter mammalian genomes. The survey exploited the current highest-quality chromosome-level assembly available for M. fascicularis, an important practical consideration because fragmented assemblies can obscure proviral structure and misplace insertions. Candidate elements were then subjected to structural annotation and phylogenetic classification, anchoring the new macaque sequences within the broader landscape of vertebrate retroviral diversity.

Classification relied on one of the most conserved regions of the retroviral toolkit: the reverse transcriptase domain of the pol gene. Because this enzyme performs the essential step of copying viral RNA into DNA, its sequence is under strong functional constraint and retains enough phylogenetic signal to place divergent elements into their correct lineages. Building multiple alignments of the recovered reverse transcriptase domains and reconstructing their evolutionary relationships, the team found that the macaque proviruses fall into betaretroviral, gammaretroviral and unclassified lineages, with the beta and gamma groups clearly predominating. This pattern mirrors what has been observed in many other mammalian genomes, where betaretroviruses and gammaretroviruses have historically been prolific colonizers of germ lines.

The compositional result carries evolutionary weight. Betaretroviruses, relatives of modern mouse mammary tumor virus and the simian retrovirus SERV, and gammaretroviruses, relatives of murine leukemia virus, differ in their envelope biology, host receptor usage and genomic preferences. A predominance of both classes suggests that the macaque lineage experienced repeated, independent waves of retroviral germline invasion rather than a single dominant radiation. Consistent with that interpretation, dating based on the divergence between the paired long terminal repeats of each provirus, which are identical at the moment of integration and accumulate mutations thereafter, indicated that the 106 loci span a broad range of integration ages, recording multiple distinct epochs of retroviral activity in the species’ ancestry.

The macaque proviruses are also distributed across all chromosomes, a pattern consistent with the idea that integration sites reflect a combination of retroviral target-site preferences and post-insertion forces such as selection, recombination and random genetic drift. Studies in human and mouse have shown that different retroviral genera favor different genomic neighborhoods, with some elements preferentially accumulating in gene-poor regions while others insert near transcription units. The chromosome-wide coverage reported for M. fascicularis means that the new dataset can support analyses of integration preference in a primate genome at a resolution previously unavailable for this species.

The biomedical significance of the work extends beyond evolutionary curiosity. The crab-eating macaque, also known as the cynomolgus macaque, is one of the most widely used primate models in drug development, infectious disease research and transplantation studies, and its endangered status in the wild makes the genomic record it carries all the more valuable to document. ERVs in macaques are directly relevant to laboratory safety as well: previous work has identified and characterized simian endogenous retroviruses in captive macaque populations in Indonesia, raising questions about how these elements behave in breeding colonies. A curated, high-confidence catalog of intact proviral loci gives researchers a framework for tracking ERV expression, recombination and potential co-option in an animal model whose transcriptomes are routinely interrogated.

The broader context of ERV biology reinforces that relevance. In humans, endogenous retroviral sequences have been co-opted for essential functions, most famously the syncytin genes derived from retroviral envelopes that mediate placental cell fusion, and ERV-derived regulatory sequences now contribute to innate immune gene networks. Deregulated ERV expression has also been implicated in a growing list of pathologies, including systemic lupus erythematosus, Parkinson’s disease, neuronal aging and cancer immunotherapy responses, where translated retroviral products can provoke interferon signaling or serve as tumor-associated antigens. Establishing which proviruses are intact in the macaque genome is therefore a prerequisite for asking whether analogous host-virus co-option and immune interactions operate in this model species.

The authors are careful to delineate the scope of their catalog. Because the screen targeted relatively intact proviruses, the dataset deliberately excludes the vastly more abundant degraded ERV fragments and solo long terminal repeats, which form when recombination between the two LTRs of an integrated provirus excises the internal sequence. Those eroded elements represent older and numerically dominant chapters of the retroviral record, and their omission means the 106 loci described here constitute a conservative, high-confidence floor rather than a complete inventory of retroviral genetic material in the macaque genome. Even so, the team notes that the curated set provides a reference resource for investigating the evolutionary history and genomic impact of preserved proviruses in an endangered primate.

The study also joins a rapidly expanding comparative effort. Recent surveys have uncovered endogenous retroviruses in red pandas, ducks and primitive ruminants, and genome-mining approaches have shown that retroviruses have pervasively invaded vertebrate genomes across the tree of life. By adding a systematic account for a close human relative, the macaque analysis helps triangulate which retroviral lineages circulated in the common ancestors of Old World monkeys and apes, and which invasions were lineage-specific. The genome assembly data underlying the work are publicly available through the National Center for Biotechnology Information, and the researchers suggest their dataset will serve as a durable foundation for exploring how viral inheritance has shaped, and continues to shape, the genome of one of biomedical science’s most important animal models.

Subject of Research: Discovery and evolutionary characterization of endogenous retrovirus proviruses in the genome of the crab-eating macaque (Macaca fascicularis)

Article Title: Discovery and evolution of endogenous retroviruses in the genome of crab-eating macaque (Macaca fascicularis)

Article References: Shi, W., Mao, L., Chen, Y., Alfred, N., Fu, Y., Bao, Y., Wang, X., Liu, Y., Yang, S., Ji, L., Zhou, C., Xu, J., Li, W., Shan, T., Wang, J., Zhang, W., & Shen, Q. (2026). Discovery and evolution of endogenous retroviruses in the genome of crab-eating macaque (Macaca fascicularis). Molecular Genetics and Genomics, 301(1), Article 189. https://doi.org/10.1007/s00438-026-02518-9

Image Credits: AI Generated

DOI: 10.1007/s00438-026-02518-9

Keywords: endogenous retroviruses, crab-eating macaque, Macaca fascicularis, retrovirus, genome evolution, provirus, phylogenetic analysis, long terminal repeats, reverse transcriptase, genomics, non-human primate model, viral fossils

The research, conducted in rhesus macaques infected with simian immunodeficiency virus, examined the consequence of administering an inhibitor of BCL-2 at the same time antiretroviral therapy was begun. BCL-2 is the founding member of a family of proteins that govern the intrinsic pathway of apoptosis, the programmed death machinery residing in the mitochondria of every nucleated cell. These proteins operate through a delicate balance: pro-survival members such as BCL-2, BCL-XL and MCL-1 sequester pro-apoptotic effectors like BAX and BAK, keeping the mitochondrial outer membrane intact. When the balance tips — through cellular stress, growth-factor withdrawal, or pharmacological inhibition — the effectors oligomerize, the membrane permeabilizes, and cytochrome c is released, committing the cell irreversibly to death. Lymphoid cells, and in particular long-lived memory T cells, depend heavily on BCL-2 for their extended lifespan, which is precisely why the latent reservoir exploits this pathway to survive the years of treatment that follow infection.

The rationale for the intervention rests on a conceptual reframing of the reservoir problem. Latency-reversing approaches attempt to shock the virus out of hiding and rely on the immune system or viral cytopathic effects to destroy the cells that harbor it. The BCL-2 strategy instead attacks the survival advantage of the infected cells themselves, arguing that if a latently infected cell can be nudged across the apoptotic threshold while the patient’s cells are protected from ongoing infection by ART, the intact reservoir should contract without the need for viral reactivation. This idea draws on clinical experience from oncology, where selective BCL-2 inhibitors such as venetoclax have transformed the treatment of chronic lymphocytic leukemia by triggering apoptosis in malignant lymphocytes that overexpress the protein. Repurposing that pharmacology for HIV cure research has long been proposed in model systems, but rigorous in vivo evidence that the approach works against the intact reservoir, in a setting that faithfully recapitulates human infection, had been lacking.

In the macaque study, animals infected with SIV received antiretroviral therapy accompanied by BCL-2 inhibition beginning at the time of treatment initiation, while control animals received ART alone. The investigators then tracked the composition of the reservoir over the course of suppression using quantitative methods capable of distinguishing intact proviruses from defective ones — an essential technical distinction, since measures that count all proviral DNA or rely solely on replication-competence assays can be dominated by defective genomes that pose no clinical threat. Single-genome sequencing approaches, in which viral genomes are amplified and analyzed individually, allow researchers to categorize each provirus as genetically intact or defective and to estimate the true size of the replication-competent reservoir. It is this intact-reservoir metric that predicts how long rebound would take after treatment interruption and that any realistic cure strategy must reduce.

The results demonstrated that the combined regimen reduced the frequency of intact SIV proviruses to a greater degree than ART alone. This finding carries significance well beyond the raw numbers. In the standard macaque model of ART suppression, the intact reservoir decays slowly and incompletely, mirroring the stubborn persistence observed in treated people living with HIV. An intervention applied at the start of therapy that accelerates this decay suggests that early intervention — the period in which the reservoir is being seeded and consolidated — represents a window of vulnerability that has been underexploited. Cells harboring latent virus during this period may be especially dependent on BCL-2-mediated survival, perhaps because they belong to recently activated, cytokine-dependent lineages that have not yet achieved the deep quiescence of long-term memory cells, or because the perturbation of the cellular environment by treatment initiation renders them more sensitive to apoptotic priming.

Timing is a theme that recurs throughout the reservoir literature, and the placement of BCL-2 inhibition at therapy initiation rather than during established suppression is one of the study’s most consequential design choices. A large body of observational work in humans has shown that the size of the reservoir is strongly determined by how quickly ART is started after infection; treatment during acute infection produces a smaller reservoir that, in rare cases, permits sustained remission after analytic treatment interruption, as famously demonstrated in the Mississippi child and a cohort of post-treatment controllers. The macaque data now suggest that pharmacological manipulation of cell-survival pathways can augment that early-treatment advantage. By pairing BCL-2 inhibition with the first days of ART, the intervention may eliminate infected cells at a stage when the reservoir is most dynamic and most chemically vulnerable, before proviruses disperse into the heterogeneous, long-lived populations that make later cure attempts so difficult.

The mechanistic logic of the approach also deserves attention. Unlike broadly neutralizing antibodies or therapeutic vaccines, which act on the viral side of the host-pathogen interface, BCL-2 inhibitors modulate host biology, raising the specter of on-target toxicity: excessive apoptosis of bystander lymphocytes, immunosuppression, or hematologic complications. The anti-apoptotic family is redundant, with different members protecting different cell lineages, and selective inhibition of BCL-2 alone is generally tolerated in leukemia patients, where the drug’s therapeutic window has been mapped in detail. Nevertheless, translating a cancer dosing schedule to an infectious-disease indication in otherwise healthy carriers requires careful attention to CD4+ and CD8+ T cell counts, neutrophil dynamics, and the possibility of transient cytokine release from dying cells. The macaque model, with its close immunological correspondence to humans and its validated SIV challenge system, provides the appropriate preclinical platform for establishing that window, and the observed reduction of the intact reservoir without catastrophic loss of immune competence represents an encouraging early signal.

Broader implications extend to the architecture of cure strategies as a whole. The field has converged on the view that no single intervention will eradicate the reservoir; combination regimens — pairing a reservoir-reduction modality with an immune effector such as broadly neutralizing antibodies, and a means of protecting uninfected cells such as long-acting antiretrovirals — are widely considered necessary. A BCL-2-directed agent could plausibly occupy the reduction slot in such combinations, working synergistically with latency-reversal approaches by first shrinking the intact pool and then rendering residual infected cells more susceptible to immune clearance. The study also reinforces a growing appreciation that the intracellular death machinery is a legitimate pharmacological target in virology, opening a search for other host-survival dependencies — metabolic, epigenetic, or signaling-based — that latently infected cells might share and that could be exploited with existing drugs.

Substantial questions remain before any human application. The durability of the reduction, its reproducibility across animals with different reservoir sizes and infection timelines, the effect of delaying inhibition until after prolonged suppression, and the interaction with viral rebound dynamics all require further investigation. Human reservoir biology differs from the macaque model in heterogeneity and scale, and the intact reservoir in chronically infected adults is orders of magnitude larger than in early-treated cases, which may limit what a survival-pathway intervention can achieve late in disease. Yet the study’s core contribution is conceptual as much as empirical: it shows in a rigorous animal model that the intact reservoir — not merely the total proviral burden — can be attacked by targeting the host determinants of cellular longevity, and that treatment initiation offers a pharmacologically exploitable moment to do so. As cure research matures beyond proof-of-concept latency reversal, strategies of this kind may help define a realistic path toward functional remission, in which residual virus is so scarce and so fragile that antiretroviral therapy can be safely suspended for extended periods.

Subject of Research: BCL-2 inhibition combined with antiretroviral therapy to reduce the intact simian immunodeficiency virus reservoir in macaques

Article Title: BCL-2 inhibition at antiretroviral therapy initiation reduces the intact SIV reservoir in macaques

Article References: Wiche Salinas, T. R., Harper, J., Deleage, C., Nguyen, K., Auger, J., Flores, H. R., Kaushik, S. R., Wilkes, A. C., Stammen, R. L., Wood, J. S., Easley, K. A., Nelson, S., Tharp, G. K., Bosinger, S. E., Cottrell, M. L., Kose, E., Immonen, T. T., Lifson, J. D., Laird, G. M., … Paiardini, M. (2026). BCL-2 inhibition at antiretroviral therapy initiation reduces the intact SIV reservoir in macaques. Nature Microbiology. https://doi.org/10.1038/s41564-026-02464-7

Image Credits: AI Generated

DOI: 10.1038/s41564-026-02464-7

Keywords: HIV cure, SIV, viral reservoir, BCL-2, apoptosis, antiretroviral therapy, latency, CD4+ T cells, macaques, provirus, treatment interruption, Nature Microbiology