Alternative strategies to control HIV

Alternative strategies to control HIV-1 infection are highly desirable. These may include manipulation of the immune response and other host factors. Prophylactic HIV-1 vaccines do not appear to show immediate promise, following the failure of a recent clinical trial (Cohen, 2007). A therapeutic HIV-1 vaccine has produced some positive results but still requires further development before it can be brought to the clinic (Pollard et al., 2014). Manipulation of host proteins is currently being evaluated, as demonstrated by a study to modify the CCR5 receptor (Didigu et al., 2014). This is a promising way to complement the current antiretroviral therapy. Nevertheless, its success relies on our understanding of the interaction between HIV-1 and cellular proteins. It has long been of interest in the field of infectious diseases that different individuals show varying degrees of susceptibility to infection. This variation may be due to differences in host protein expression. For example, one of the most well-known susceptibility-determining factors for HIV infection is the CCR5 co-receptor. A deletion of 32bp in the CCR5 receptor confers a much reduced susceptibility to HIV-1 infection for the host (Liu et al., 1996; Dean et al., 1996; Samson et al., 1996). A number of other enhancing and restrictive factors on HIV-1 replication have been proposed, including TRIM5α, APOBEC3 family, BST-2/tetherin, HLA-G, and microRNAs (Lever and Lever, 2011; da Silva et al., 2014; Napuri et al., 2013). However, whether they affect individual susceptibility to HIV-1 infection remains elusive (Imahashi et al., 2014). Viral infection begins with the binding of a cellular receptor, followed by viral entry and replication. Many cellular factors interact with viral genes for the completion of the replication carnitine palmitoyltransferase and production of mature virions. We reasoned that cellular and viral protein interactions may contribute to varying degrees of susceptibility to viral infection. Hence, we examined Vpr-associated cellular proteins and studied their roles in human HIV-1 infection. In a previous study, by yeast-two-hybrid assay we identified several cellular proteins that interact with HIV-1 Vpr (Yedavalli et al., 2005). Of them, DNAJB6 is a homolog of heat shock protein 40 (HSP40), and has two splice isoforms: the large form MRJ-L and the small form MRJ-S (Hanai and Mashima, 2003). Prompted by the notion that DNAJ is a heat shock protein which may contribute to HIV-1 replication, we investigated the expression of DNAJB6 in lymphocytes and monocyte-derived macrophages (MDMs) which are considered the major targets of early HIV-1 infection.
Materials and Methods
Results
Discussion Many cellular factors participate in the replication of a virus. A better understanding of the cellular factors involved in viral infection can lead to better antiviral strategies, especially for a difficult virus like HIV-1. We are particularly interested in cellular factors that exhibit different expression patterns between individuals, indicating the presence of natural polymorphisms and which could therefore be amenable to manipulation without grave adverse effects. Vpr is an important auxiliary gene of HIV-1 with multiple functions (Yedavalli et al., 2005; Kogan and Rappaport, 2011). Interestingly, we found that MRJ-L, a cellular protein interacting with Vpr, is enriched when monocytes differentiate into macrophages and has varying expression levels among macrophages from different individuals. Macrophages play a unique role in HIV-1 infection; among all the quasi-species of HIV-1 in an infected individual, macrophage-tropic strains are preferentially transmitted to a new host (van\'t Wout et al., 1994; Zhu et al., 1993). When HIV-1 is transmitted to a new host at the mucosal surface, the virus has to undergo ample local expansion to enable dissemination to local lymphoid tissues, or the infection is aborted (Haase, 2010). As macrophages are the primary targets of HIV-1, the transmitted virus should replicate efficiently in macrophages. For non-dividing cells such as macrophages, delivery of the HIV-1 pre-integration complex to the nucleus is a critical and likely rate-limiting step (Segura-Totten and Wilson, 2001). Vpr is primarily responsible for this nuclear transport, and the presence of sufficient MRJ-L protein appears to be essential for Vpr to perform this function.