Retrovirology : research and treatment最新文献

Similar to HIV, FIV uses a two-receptor mechanism to infect CD4(+) T cells, the primary target cells in the cat. The T cell activation marker, CD134, serves as a primary binding receptor similar to the role of CD4 for HIV and facilitates interaction with the entry receptor, CXCR4. Heparan sulfate proteoglycans (HSPG) can also act as binding receptors for certain tissue culture adapted FIV and HIV isolates. In the present study, we employed site-directed mutagenesis to investigate the importance of specific residues on the FIV envelope for CD134 and HSPG interactions. We show that certain mutations that disrupt CD134 interactions facilitate HSPG binding by FIV-PPR. In particular, an E407K mutation at the base of the V3 loop knocks out CD134 binding; enhances HSPG binding; and in combination with additional Env mutations E656K and V817I increases entry into CD134(-), CXCR4(+) target cells by greater than 80-fold over wild type FIV-PPR. The CD134-independent mutant, termed FIV-PPRcr, exhibits a broadened host cell range, but also becomes readily susceptible to CD134-dependent neutralizing monoclonal antibodies. The findings are consistent with the notion that FIV-PPRcr Env has an "open" conformation that readily associates with CXCR4 directly, similar to wild type FIV-PPR Env after CD134 binding. The findings highlight the utility of a two-receptor mechanism that allows FIV V3 residues critical for CXCR4 binding to remain cryptic until reaction occurs with the primary binding receptor, thus thwarting immune surveillance.

Mozambique has severe resource constraints, yet with international partnerships, the nation has placed over 145,000 HIV-infected persons on antiretroviral therapies (ART) through May-2009. HIV clinical services are provided at > 215 clinical venues in all 11 of Mozambique's provinces. Friends in Global Health (FGH), affiliated with Vanderbilt University in the United States (US), is a locally licensed non-governmental organization (NGO) working exclusively in small city and rural venues in Zambézia Province whose population reaches approximately 4 million persons. Our approach to clinical capacity building is based on: 1) technical assistance to national health system facilities to implement ART clinical services at the district level, 2) human capacity development, and 3) health system strengthening. Challenges in this setting are daunting, including: 1) human resource constraints, 2) infrastructure limitations, 3) centralized care for large populations spread out over large distances, 4) continued high social stigma related to HIV, 5) limited livelihood options in rural areas and 6) limited educational opportunities in rural areas. Sustainability in rural Mozambique will depend on transitioning services from emergency foreign partners to local authorities and continued funding. It will also require "wrap-around" programs that help build economic capacity with agricultural, educational, and commercial initiatives. Sustainability is undermined by serious health manpower and infrastructure limitations. Recent U.S. government pronouncements suggest that the U.S. President's Emergency Plan for AIDS Relief will support concurrent community and business development. FGH, with its Mozambican government counterparts, see the evolution of an emergency response to a sustainable chronic disease management program as an essential and logical step. We have presented six key challenges that are essential to address in rural Mozambique.

Human immunodefi ciency virus type-1 integrase (IN) is a new and novel target for inhibitors. Strand transfer inhibitors effectively prevent concerted integration of viral DNA by IN into the host chromosomes. Raltegravir is the fi rst approved strand transfer inhibitor for the treatment of HIV-1/AIDS. We propose a mechanistic hypothesis as to "when and where" these inhibitors are active in virus-infected cells. Using native agarose gel electrophoresis, we identified a transient synaptic complex (SC) wherein IN non-covalently juxtaposes two viral DNA ends. SC possesses many properties associated with the cytoplasmic preintegration complex (PIC) in infected cells, including concerted integration. Our results show that the strand transfer inhibitors effectively "trap" or inactivate the SC preventing concerted integration. It follows that the IN-viral DNA complex is "trapped" by the inhibitors via a transient intermediate within the cytosolic PIC before entry into the nucleus.

HIV-1-associated dementia (HAD) describes the cognitive impairments and behavioral disturbances which afflict many HIV-infected individuals. Although the incidence of HAD has decreased significantly in the era of HAART, it remains a significant complication of HIV-1 infection as patients with acquired immune deficient syndrome (AIDS) live longer, antiretroviral drugs remain unable to effectively cross the blood-brain barrier (BBB), and HIV-1 resistance grows due to viral strain mutation. Although the precise mechanism leading to HAD is incompletely understood, it is commonly accepted its progression involves a critical mass of infected and activated mononuclear phagocytes (MP; brain perivascular macrophages and microglia) releasing immune and viral products in brain. These cellular and viral products induce neuronal dysfunction and injury via various signaling pathways. Emerging evidence indicates that voltage-gated potassium (K(v)) channels, key regulators of cell excitability and animal behavior (learning and memory), are involved in the pathogenesis of HAD/HAND. Here we survey the literature and find HAD related alterations in cellular and viral products can alter MP and neuronal K(v) channel activity, leading to MP and neuronal dysfunction and cognitive deficits. Thus, MP and neuronal K(v) channels may be a new target in the effort to develop therapies for HAD and perhaps other inflammatory neurodegenerative disorders.