Developing biological interventions to control human immunodeficiency virus (HIV) replication in the absence of antiretroviral therapy (ART) could contribute to the development of a functional cure. As a potential alternative to ART, the interleukin-15 (IL-15) superagonist ALT-803 has been shown to boost the number and function of HIV-specific CD8 T and NK cell populations Four simian immunodeficiency virus (SIV)-positive rhesus macaques, three of whom possessed major histocompatibility complex alleles associated with control of SIV and all of whom had received SIV vaccine vectors that had the potential to elicit CD8 T cell responses, were given ALT-803 in three treatment cycles. The first and second cycles of treatment were separated by 2 weeks, while the third cycle was administered after a 29-week break. ALT-803 transiently elevated the total CD8 effector and central memory T cell and NK cell populations in peripheral blood, while viral loads transiently decreased by ∼2 logs in all animals. Virus suppression was not sustained as T cells became less responsive to ALT-803 and waned in numbers. No effect on viral loads was observed in the second cycle of ALT-803, concurrent with downregulation of the IL-2/15 common γC and β chain receptors on both CD8 T cells and NK cells. Furthermore, populations of immunosuppressive T cells increased during the second cycle of ALT-803 treatment. During the third treatment cycle, responsiveness to ALT-803 was restored. CD8 T cells and NK cells increased again 3- to 5-fold, and viral loads transiently decreased again by 1 to 2 logs. Overall, our data show that ALT-803 has the potential to be used as an immunomodulatory agent to elicit effective immune control of HIV/SIV replication. We identify mechanisms to explain why virus control is transient, so that this model can be used to define a clinically appropriate treatment regimen.

Tuberculosis (TB), caused by , is the leading cause of death among human immunodeficiency virus (HIV)-positive patients. The precise mechanisms by which HIV impairs host resistance to a subsequent infection are unknown. We modeled this coinfection in Mauritian cynomolgus macaques (MCM) using simian immunodeficiency virus (SIV) as an HIV surrogate. We infected seven MCM with SIVmac239 intrarectally and 6 months later coinfected them via bronchoscope with ∼10 CFU of Another eight MCM were infected with alone. TB progression was monitored by clinical parameters, by culturing bacilli in gastric and bronchoalveolar lavages, and by serial [F]fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging. The eight MCM infected with alone displayed dichotomous susceptibility to TB, with four animals reaching humane endpoint within 13 weeks and four animals surviving>19 weeks after infection. In stark contrast, all seven SIV animals exhibited rapidly progressive TB following coinfection and all reached humane endpoint by 13 weeks. Serial PET/CT imaging confirmed dichotomous outcomes in MCM infected with alone and marked susceptibility to TB in all SIV MCM. Notably, imaging revealed a significant increase in TB granulomas between 4 and 8 weeks after infection in SIV but not in SIV-naive MCM and implies that SIV impairs the ability of animals to contain dissemination. At necropsy, animals with preexisting SIV infection had more overall pathology, increased bacterial loads, and a trend towards more extrapulmonary disease than animals infected with alone. We thus developed a tractable MCM model in which to study SIV- coinfection and demonstrate that preexisting SIV dramatically diminishes the ability to control coinfection.

We previously showed that the cellular proteins ZEB1 and ZEB2/SIP1 both play key roles in regulating the latent-lytic switch of Epstein-Barr Virus (EBV) by repressing BZLF1 gene expression. We investigated here the effects of cellular microRNA (miRNA) 200 (miR200) family members on the EBV infection status of cells. We show that miR200b and miR429, but not miR200a, can induce EBV-positive cells into lytic replication by downregulating expression of ZEB1 and ZEB2, leading to production of infectious virus. The levels of miR200 family members in EBV-infected cells strongly negatively correlated with the levels of the ZEBs (e.g., ؊0.89 Reactivation of EBV out of latency into lytic replication is necessary for the viral progeny to pass from host to host. It occurs naturally in infected individuals at a low frequency; periodic shedding of the virus into saliva allows for transmission (75). It remains unclear how reactivation occurs in vivo. The product of the BZLF1 gene, known as BZLF1 (also called ZEBRA, Z, Zta, and EB1), is a key player in switching EBV from latency into lytic replication in cells in culture (16,17,25,80; reviewed in references 74 and 75).BZLF1 is a multifunctional DNA-binding protein belonging to the bZIP member of transcription factors (12). By activating transcription of other viral genes and binding to the viral origin of lytic replication, oriLyt, BZLF1 can induce viral genome replication and expression of a cascade of other EBV lytic genes necessary for packaging of the genome into virion particles and exit from the host cell (40,52,74,76,77). BZLF1 can also interact with several cellular proteins, affecting their activities and cellular localization, further contributing to viral reactivation (61, 74). Because of BZLF1's central role in reactivation of EBV out of latency into lytic replication, factors that regulate its expression have been implicated as potential therapeutics for treating patients with EBV-associated malignancies.Our laboratory previously reported that the cellular proteins ZEB1 (also known as ␦EF1, TCF8, AREB6, ZFHEP, NIL-2A, ZFHX1A, and BZP) and ZEB2 (also known as SIP1, SMA-DIP1, ZFHX1B, and KIAA0569) can both bind to a sequence element, termed ZV, located within the BZLF1 promoter, Zp (22,47,48,92); a second element, ZVЈ, synergizes with the ZV element for higher-affinity binding of the ZEBs to Zp via their two zinc fingers (Fig. 1A) (X. Yu, P. McCarthy, D. Gorlen, and J. E. Mertz, unpublished data). Both of these ZEB family members bind to target DNA via E-box-binding sequences resembling 73). Depending on interactions with coactivators and corepressors and associations with histone deacetylases (HDACs) (68,71,84), ZEB1 can either activate or repress transcription of its target genes (68,70,72); to date, ZEB2 has been reported only to repress transcription (67). We showed that exogenous expression of either ZEB1 or ZEB2 leads to repression of transcription driven from Zp in transient transfection assays (22,48,92). Mutation of the ZV element in the context of the B9...

Tuberculosis (TB) is the leading infectious cause of death among people living with HIV. People living with HIV are more susceptible to contracting Mycobacterium tuberculosis and often have worsened TB disease. Understanding the immunologic defects caused by HIV and the consequences it has on M. tuberculosis coinfection is critical in combating this global health epidemic. We previously showed in a model of SIV and M. tuberculosis coinfection in Mauritian cynomolgus macaques (MCM) that SIV/M. tuberculosis–coinfected MCM had rapidly progressive TB. We hypothesized that pre-existing SIV infection impairs early T cell responses to M. tuberculosis infection. We infected MCM with SIVmac239, followed by coinfection with M. tuberculosis Erdman 6 mo later. Although similar, TB progression was observed in both SIV+ and SIV-naive animals at 6 wk post–M. tuberculosis infection; longitudinal sampling of the blood (PBMC) and airways (bronchoalveolar lavage) revealed a significant reduction in circulating CD4+ T cells and an influx of CD8+ T cells in airways of SIV+ animals. At sites of M. tuberculosis infection (i.e., granulomas), SIV/M. tuberculosis–coinfected animals had a higher proportion of CD4+ and CD8+ T cells expressing PD-1 and TIGIT. In addition, there were fewer TNF-producing CD4+ T cells in granulomas of SIV/M. tuberculosis–coinfected animals. Taken together, we show that concurrent SIV infection alters T cell phenotypes in granulomas during the early stages of TB disease. As it is critical to establish control of M. tuberculosis replication soon postinfection, these phenotypic changes may distinguish the immune dysfunction that arises from pre-existing SIV infection, which promotes TB progression.

N-803 is a drug that boosts the immune cells involved in combating HIV/SIV infection. Here, we found that in SIV + rhesus macaques that were not on antiretroviral therapy, N-803 increased the proliferation and potential capacity for killing of the SIV-specific immune cells to a greater degree in animals that spontaneously controlled SIV than in animals that did not control SIV.