HIV-2 inhibits HIV-1 gene expression via two independent mechanisms during cellular co-infection

Human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). The two main forms of HIV are HIV-1 and HIV-2; in the clinic, each is predominantly found in the context of monoinfection. However, dual infections are found in regions where HIV-1 and HIV-2 coexist, such as West Africa. Both viruses can induce AIDS; however, HIV-2 is generally less pathogenic than HIV-1 and progresses more slowly to AIDS. Additionally, there are reports that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, and in cell culture. However, the mechanisms underlying these protective effects are not well understood. To decipher these mechanisms, we performed dual infections with HIV-1 and HIV-2 in cell culture. We demonstrated that HIV-1 and HIV-2 can co-infect individual cells. HIV-2 infection was found to inhibit HIV-1 infection when performed prior to or simultaneously with HIV-1 infection. Two distinct mechanisms were identified. First, HIV-2 induces an interferon (IFN) response that broadly inhibits gene expression. Second, in the absence of IFN production, HIV-1-specific inhibition was found to be conferred by the HIV-2 trans-activation response (TAR) element. The HIV-2 TAR (TAR-2) element appears to inhibit HIV-1 long terminal repeat (LTR) promoter activity through competition with the HIV-1 TAR element for HIV-1 Tat binding. We show that this results in suppression of HIV-1 LTR-driven transcription by stalling RNA polymerase II early transcription complexes at the HIV-1 LTR promoter region.IMPORTANCETwenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first that these viruses can co-infect individual cells. Under specific conditions, HIV-2 inhibits HIV-1 through two distinct mechanisms, a broad-spectrum interferon response and an HIV-1-specific inhibition conferred by the HIV-2 TAR. The former could play a prominent role in dually infected individuals, whereas the latter targets HIV-1 promoter activity through competition for HIV-1 Tat binding when the same target cell is dually infected. That mechanism suppresses HIV-1 transcription by stalling RNA polymerase II complexes at the promoter through a minimal inhibitory region within the HIV-2 TAR. This work delineates the sequence of appearance and the modus operandi of each mechanism. Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first that these viruses can co-infect individual cells. Under specific conditions, HIV-2 inhibits HIV-1 through two distinct mechanisms, a broad-spectrum interferon response and an HIV-1-specific inhibition conferred by the HIV-2 TAR. The former could play a prominent role in dually infected individuals, whereas the latter targets HIV-1 promoter activity through competition for HIV-1 Tat binding when the same target cell is dually infected. That mechanism suppresses HIV-1 transcription by stalling RNA polymerase II complexes at the promoter through a minimal inhibitory region within the HIV-2 TAR. This work delineates the sequence of appearance and the modus operandi of each mechanism.