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Interferon types-I/II (IFN-αβ/γ) secretions are well-established antiviral host defenses. The human immunodeficiency virus (HIV) particles are known to prevail following targeted cellular interferon secretion. CD4+ T-lymphocytes are the primary receptor targets for HIV entry, but the virus has been observed to hide (be latent) successfully in these cells through an alternate entry route via interactions with LFA1. HIV facilitates its post-entry latency-driven mode of hiding through these interactions to displace or inhibit ISG15 by forming the HIV1-LFA1 complex in lieu of ISG15-LFA1, which would at least transiently halt and bypass type-I IFN secretion. This could explain why the elimination of HIV from cellular hideouts is difficult. Hence, HIV clearance needs to be addressed to reverse its latency in LFA1+ T-lymphocytes and CD34+/CD133+ early progenitor stem cells. In the context of hematopoietic or endothelial stem-progenitor cells (HSPC/ESPC), we discuss the potential role of LFA1 in HIV permissiveness and latency in LFA1-CD34+/CD133+ versus LFA1+CD34+/CD133+ HSPCs/ESPCs. In HIV latency, the viral particles may remain engaged on the naïve-resting cells’ LFA1, which are then unable to accommodate the ISG15 molecules owing to conformational changes induced upon occupation by the virus at the ISG15-LFA1 binding or interaction sites through halting of the subsequent downstream type-II IFN secretion. Viral binding to LFA1, including its transfer through activated-naïve cell–cell contacts may be a key step that needs to be addressed to prevent “transient or partial” virus-induced shutdown of type-I IFN secretion. This process allows an alternate viral entry and hideout site via LFA1. The subsequent administration of recombinant ISG15 may ensure sufficient type I/II IFN release to promote, enhance, or sustain the innate immune responses. Thus, combination antiviral therapies could potentially include exogenous ISG15 to maintain or sustain biologically and clinically relevant ISG15-LFA1 interactions. In addition to alternating with co-challenges of PKC-pro-LRA-drug modulators, this is administered post (antiretroviral therapy) and continued with periodic ART until permanent elimination of viral resurgence and latency is achieved in patients with HIV/AIDS. This triple-combination drug regimen is expected to pave the path for systemic virus clearance in vivo.

Cytopenias are a common occurrence due to abnormal hematopoiesis persistent in patients suffering from and advancing with HIV/AIDS. In order to develop efficacious therapies against cytopenias, it is necessary to understand the mechanisms by which HIV infection affects the differentiation of hematopoietic stem-progenitor cells (HSPCs), causing hematopoietic inhibition, that leads to hematological disorders. Currently, only the antiretrovirals that are being used to treat HIV infection and indirectly lower the levels of virus replication also co-attenuate cytopenias. The evidence available suggests that this indirect efficacy may not prevail for the lifetime of the infected patients, and the acquired immunodeficiency can overtake the beneficial consequences of decreased virus replication. As cited in this article, we and our colleagues are the first to make a foray into the involvement of microRNAs and their use as potential interventional treatments for the cytopenias that occur with HIV/AIDS. Herein, we progressed further in the direction of the mechanisms of the involvement of homeobox gene regulation to cause cytopenias. We had previously shown that HIV-1 inhibits multi-lineage hematopoiesis of the CD34+ cells using SCID-hu Thy/Liv animals in vivo. Furthermore, we demonstrated that the virus-induced hematopoietic inhibition occurred despite the CD34+ cells being resistant to HIV-1 infection. We set out to search for the specific host factors secreted by CD4+ T-cells that likely participate in the inhibition of hematopoiesis of the HIV infection-resistant CD34+ cells. More recently, we reported the identification of virus-infected CD4+ thymocyte-secreted miRNA-15a and miRNA-24 and that their differential expression following HIV infection causes the indirect inhibition of hematopoiesis. We then hypothesized that the observed miRNA differential expression in the virus-infected T-cells causes the abnormal regulation of homeobox (HOX) gene-encoded transcriptomes in the CD34+ cells, affecting specific MAPK signaling and CD34+ cell fate, thereby disrupting normal hematopoiesis. We present that in HIV infection, miRNA-mediated post-transcriptional dysregulation of HOXB3 mRNA inhibits multi-lineage hematopoiesis, which translates into hematological disorders in virus-infected patients with HIV/AIDS. These observations portend specific microRNA candidates for potential efficacy against the virus-induced cytopenias that are otherwise not treatable by the existing HAART/ART regimens, which are primarily designed and applicable for the attenuation of virus replication.

The multitude of cellular types can be expected to behave differently when receiving invading pathogens such as mammalian viruses. The nature-dictated causes for such intrinsic cellular diversity become the criteria for the emergence of specific virus-receptor interactions on that particular host cellular surface, in order to accommodate contact with various other living entities whether desirable to the host or not. At present, we are presented with an example of two contrasting behaviours wherein the well-known HIV-1 and the more recently emergent SARS-CoV-2 cause adverse consequences to the differentiation and functions of progenitor stem cells. These include the two different downstream multipotent CD34+ hematopoietic (HSPC) and CD133+ endothelial (ESPC) stem-progenitor cells of their common pluripotent hemangioblast precursors. The two viruses target the respective endothelial and hematopoietic stem-progenitor cells to thrive upon the relevant host cellular surrounded stromal microenvironments by adopting reciprocally-driven mechanistic routes, which incidentally cause pathogenesis either directly of ESPC (SARS-CoV-2), or indirectly of HSPC (HIV-1). HIV-1 utilizes the CD4+ T-lymphocyte receptor thereby advancing pathogenesis indirectly to the CD34+ HSPC. SARS-CoV-2 directly targets the CD133+ ESPC via ACE2 receptor causing cytokine storms of the CD4+ T-lymphocytes. In this manner, these two viruses cause and extend their damage to the other cellular sub/types coexisting in the host cellular microenvironments. The infected individuals require clinical interventions that are efficacious to prevent cellular dysfunction and ultimate cell depletion or death. We infer from these viruses mediated pathogeneses mechanisms a potential common origin of microRNA molecular therapies to address cellular dysfunctions and prevent cell loss.