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

This is the authors' abstract. We don't add key points for this paper.

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. IMPORTANCE 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.