There are two types of human immunodeficiency virus: type 1 (HIV-1) and type 2 (HIV-2). HIV–1 is the most widespread type and accounts for 95% of all infections worldwide.
HIV is a virus that damages the immune system and, without treatment, a person infected with HIV can develop acquired immunodeficiency syndrome (AIDS). AIDS is a chronic, potentially life-threatening condition where the immune system is weakened leaving your body vulnerable to deadly infections.
Type I interferon (IFN) induction and the consequent expression of thousands of interferon-stimulated genes (ISGs) during infection are crucial in the induction of an antiviral state. Despite the described capacity of type I IFN to disrupt the replication of HIV-1, many key issues remain poorly understood, including the precise functions of the vast majority of ISGs, what molecular mechanism are employed.
Therefore, the identification of novel ISGs involved in the IFN-induced block to HIV-1 infection and mechanistic underpinnings are crucial for the therapeutic application of IFNs during HIV-1 infection, and possibly other chronic infections.
In a recent publication in Nature Microbiology, the authors demonstrated that IFN-mediated stimulation of the immunoproteasome, a proteasome isoform mainly present in immune cells, enables human TRIM5alpha as a key effector in the IFN-induced suppression of HIV-1 infection, including validation in primary human CD4+ T cells, the primary cell target of HIV.
Importantly, though rhesus macaque TRIM5alpha was discovered as an HIV-1 restriction factor in 2004, human TRIM5alpha has not generally been ascribed significant HIV-1 inhibitory function. In fact, TRIM5alpha proteins have been regarded as being virtually inactive against viruses in their natural hosts, but have been assigned as important inhibitors of cross-species transmissions. Therefore, the present study changes the long held dogma in the retrovirus field that human TRIM5alpha is virtually ineffective at inhibiting HIV-1.
What differentiates this study from others is that experiments were undertaken in the presence of interferon, as described above, a cytokine with well-established HIV-1 suppressor activity. In addition, this study demonstrates that loss-of-function screenings are an excellent complement to overexpression screenings because gene-by-gene strategies miss the identification of proteins that function in combination with other proteins.
Reference: Immunoproteasome activation enables human TRIM5α restriction of HIV-1.