More than 1.2 million Americans and 37.8 million people worldwide are currently living with HIV. For these individuals, and for those who will become infected with HIV, any future vaccine will come too late, and effective antiviral therapies must be used to combat their HIV infections and HIV-associated cancers. Recently, work in the HIV Dynamics and Replication Program (HIV DRP) has been extended to include the innate immune response to viruses other than HIV, and studies of cancer viruses.
The application of therapies using combinations of antiviral drugs has shown that HIV replication in infected people can be suppressed, which provides considerable and long-lasting clinical improvement. These therapies have helped large numbers of infected individuals live relatively normal lives. Most importantly, they validate the concept that antiviral drugs can offer long-term relief to individuals with HIV infections. However, current therapies do not eliminate the virus from infected individuals; thus, lifelong treatment is required. This long-term therapy is associated with a number of challenges, including toxicity, inadequate adherence, chronic immune activation, and, in some cases, the appearance of drug-resistance mutations. Thus, there remains an urgent need to understand how HIV persists despite treatment and develops resistance to drugs; this new information can be used to develop strategies toward HIV achieving remission without antivirals and to develop long-acting drugs with reduced toxicity for the treatment of HIV infections.
The HIV DRP was formed in 1997 as the HIV Drug Resistance Program, with the mission of conducting and fostering multidisciplinary basic, translational, and clinical research focused on problems related to drug-resistant HIV. The Program has built on the existing strengths of the NCI’s basic and clinical research programs in retrovirology, drug discovery, AIDS, and AIDS malignancies, exploiting studies in structural biology, biochemistry, virology, virus-host interaction, evolution, and in vivo virus biology to better understand mechanisms of retroviral replication, persistence, and coinfections. These are areas of critical importance to the AIDS epidemic, and they raise both basic and clinical research challenges whose solution will enhance our understanding of fundamental aspects of virology and cell biology and guide the development of new effective therapeutics and therapies. Although the Program focuses primarily on HIV, drug resistance is a major concern for other infectious agents as well as cancer, and it is likely that our research will be beneficial in these and other areas. As noted earlier, the research that is being conducted in the HIV DRP has recently expanded beyond HIV to include studies of innate immunity and cancer viruses.
Because antiviral therapies for HIV are highly effective, some of the focus in the field, and within the HIV DRP, has shifted toward questions that include, but are not limited to, the interactions of HIV (and other viruses) with the host. These include basic and molecular questions involving the host cell factors that HIV exploits during its replication and factors that the host cell uses to help control the replication of HIV and other viruses. There is also an interest in how the virus is able to persist in infected individuals who have been successfully treated with antiviral drugs for many years. It now appears that some HIV-infected cells in individuals can grow and divide. This clonal expansion helps the DNA copies of the viral genome carried by the expanded cell clones to persist and contributes to the reservoir that has made developing a cure for HIV infections a challenging goal.
The scope of research conducted by HIV DRP scientists has expanded over the years to encompass a broader range of important problems in virus biology. Thus, in 2015, the name of the Program was changed to HIV Dynamics and Replication to better capture the breadth of the research carried out by the Program.
Research Interests and Goals
The HIV DRP comprises a basic research component (Retroviral Replication Laboratory, RRL) and a clinical/translational component (Host-Virus Interaction Branch, HVIB).
The RRL focuses on understanding events in the viral replication cycle, from the initial interactions of the virus and host cell; through reverse transcription, nuclear import, and integration; to RNA trafficking, virus assembly, release, and maturation. Studies also focus on host restriction factors, antiviral immunity, and genetic variation and evolution of HIV and other viruses, particularly viruses that can cause cancer in humans.
• The Retrovirus Assembly Section, headed by Alan Rein, investigates virus assembly and maturation, with a focus on human and murine retroviruses. Other research interests include structure-function relationships in viral proteins and viral RNA, retrovirus biology, and cellular defense mechanisms against retroviruses, such as restriction by SERINC5 and APOBEC3.
• The Vector Design and Replication Section, directed by Stephen H. Hughes, has two principal areas of research: developing inhibitors to HIV-1 reverse transcriptase and integrase, and elucidating the link between HIV-1 integration sites in infected individuals and viral persistence in vivo.
• The Virus-Cell Interaction Section, under the direction of Eric O. Freed, is interested in the assembly and release of HIV-1 from infected cells, Env incorporation, the host factors that both promote and restrict the late events in HIV-1 replication, and virus maturation. Dr. Freed has a long-term program focused on developing maturation inhibitors, and his group recently discovered a role for HIV-1 Env in broadly rescuing blocks to virus replication in vitro, including those conferred by antiretrovirals.
• The Viral Recombination Section, directed by Wei-Shau Hu, studies how HIV transfers genetic information to its progeny. This Section combines state-of-the-art microscopy techniques with sophisticated virology and molecular biology approaches to study RNA genome packaging, virus assembly, and the biology of the full-length RNA. Dr. Hu also uses model systems and clinical isolates to study the mechanisms of reverse transcription, recombination, and virus evolution.
• The Viral Mutation Section, headed by Vinay K. Pathak, focuses on elucidating the early stages of HIV-1 replication by developing new imaging tools and methods to analyze early replication events, including nuclear import, intranuclear transport and nuclear localization, uncoating, and proviral transcription. This Section also focuses on elucidating the structure and function of HIV-1 Vif and APOBEC3 restriction factors and developing new gene therapy strategies for HIV-1 treatment and functional cure.
• The Antiviral Immunity and Resistance Section, led by Alex Compton, combines approaches in virology, cell biology, and evolutionary biology to study cell-intrinsic mechanisms of virus defense. Dr. Compton has made major contributions to our understanding of the antiviral activity of the IFITM protein family in the context of HIV-1, influenza A, and Zika virus infections and discovered regulatory mechanisms that control IFITM protein expression, which can be exploited for lentiviral vector-mediated gene delivery. Most recently, this Section is investigating roles for the IFITM proteins during cancer development.
• The Tumor Virus RNA Biology Section, under the direction of Zhi-Ming (Thomas) Zheng, is interested in viral and host gene expression and posttranscriptional regulation. Using papillomaviruses and Kaposi’s sarcoma-associated herpesvirus as model virus systems, this Section has pursued a long-term focus on how protein-nucleic acid and protein-protein interactions regulate the transcription of viral and host genes, RNA splicing and polyadenylation, RNA stability, export, and translation in the context of viral infections and carcinogenesis.
The HVIB carries out translational and clinical studies to elucidate HIV-host interactions and to devise approaches to understand, and eventually eliminate, HIV reservoirs. This Branch has studied the evolution and clinical significance of HIV drug resistance in vivo, and the persistence of HIV-infected cells in individuals on antiretroviral therapy (ART). The HVIB contains two research sections, headed by Frank Maldarelli and Mary F. Kearney. Stephen Hughes serves as Chief of the HVIB and is engaged in extensive collaborative interactions with this Branch. John W. Mellors and John M. Coffin, through contracts with the University of Pittsburgh and Tuft University, respectively, also play important roles in the research mission of the HVIB.
• The Clinical Retrovirology Section, headed by Frank Maldarelli, uses clinical protocols at the NIH Clinical Center to investigate how HIV infections persist even after years of successful ART and what constitutes the reservoir of infected cells that leads to reemergence of the virus if ART is interrupted or inadequate. The Section also studies the population genetics of HIV prior to and following initiation of ART to understand the emergence of resistance within individuals. Dr. Maldarelli divides his time between the Bethesda campus of the NIH, where he works in conjunction with the NIAID/CCMD AIDS clinical program and the NCI HIV and
/AIDS Malignancy Branch, and the Frederick campus, where his laboratory is located.
• The Translational Research Section, under the direction of Mary F. Kearney, analyzes viral RNA and DNA sequences present in cells and plasma. This Section performs studies of HIV genetics in individuals, viral persistence during therapy, and the development and evolution of drug resistance.
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The HIV DRP is a research program of the Center for Cancer Research (CCR) at the National Cancer Institute (NCI), National Institutes of Health (NIH).