Gene Mutations Tied to Immune Comeback during Therapy for HIV-1

Researchers with the Infectious Disease Clinical Research Program (IDCRP) at the Uniformed Services University of the Health Sciences (USU) here and the University of Texas at San Antonio have published a patient outcome study in the March 30 online edition of Nature Medicine that may signal a need for a change of thought in the management of HIV. The IDCRP was established in 2005 by the National Institutes of Allergy and Infectious Diseases and USU as a major new initiative to focus on clinical infectious diseases of military importance. This collaborative program encourages the exchange of scientific ideas and fosters progress in fighting new health challenges. Among the IDCRP collaborators in this program are Drs. Mathew Dolan, Brian Agan and Maj. Vince Marconi at Wilford Hall Medical Center, San Antonio.

The IDCRP is headquartered within the Department of Preventive Medicine and Biometrics (PMB) at USU. The Principal Investigator, CAPT Gerald V. Quinnan, Jr., M.D., is also the chair of PMB. According to Quinnan, “This research is another accomplishment of the IDCRP in our efforts to connect with other researchers throughout the country and bring new insights to the care and prevention of infectious diseases including HIV.”

According to the press release from University of Texas, San Antonio:

“A new study by U.S. scientists provides compelling evidence that two genes are linchpins in defining the course of immune restoration in HIV-positive individuals undergoing virus-suppressing therapy.

Nature Medicine, one of the world’s highest-impact journals, posted the study online March 30. The findings explain why some subjects’ immune systems only weakly recover T-cell counts and function, despite stunting of HIV-1 replication by highly active antiretroviral therapy (HAART), while others’ immune systems roar back.

The two genes are CCR5, an HIV-1 co-receptor, or portal of entry, for the virus into CD4+ T cells, and CCL3L1, an HIV-suppressing molecule that binds to CCR5.

“The new results suggest that we may be able to personalize the treatment of HIV as we might be able to predict, based on the presence of these gene variations, whether someone will have a better or worse immunological response when taking HAART,” said lead author Sunil K. Ahuja, M.D., professor of medicine, microbiology, infectious diseases and biochemistry at The University of Texas Health Science Center at San Antonio and director of the Veterans Administration Center for AIDS and HIV Infection at the South Texas Veterans Health Care System in San Antonio. He holds the university’s President’s Council Chair for Excellence in Medical Research.

“We categorized the copy number of the CCL3L1 gene and variations in the CCR5 gene into three categories designated as high, moderate and low genetic risk groups,” said Matthew Dolan, M.D., co-lead author who also helped oversee the cohort of subjects at Wilford Hall Medical Center, San Antonio, which contributed to this study. “Those HIV-positive persons categorized into the low genetic risk group had the best recovery in CD4+ T cell counts during HAART, while those in the high rsk category had a less successful response followed by a CD4+ T cell decline.”

A 2005 study by Dr. Ahuja and colleagues suggested that individuals with fewer copies of CCL3L1 genes than the average found in people from their ethnic background have increased risk of acquiring HIV-1 infection and progressing faster to AIDS. Also, previous studies by these researchers defined the CCR5 variations that confer protection.

“It is noteworthy that in previous studies we found the same low genetic risk group showed less CD4+ T-cell depletion in untreated HIV-positive persons” said Brian Agan, M.D., a co-author also from Wilford Hall Medical Center. Maj. Vince Marconi, M.D., another co-author from the same institution, said, “We feel these are clinically relevant findings, as the low genetic risk group constituted nearly 50 percent of the cohort.” “It is for these reasons that we think CCL3L1-CCR5 genetic makeup might be a critical modulator of HIV disease course and therapy response” added Hemant Kulkarni, M.D., a co-author from the Veterans Administration HIV/AIDS Center.

Mike McCune, M.D., Ph.D., Senior Associate Dean of Clinical and Translational Research at The University of California, San Diego, hailed the study as a landmark. “By showing that the same genetic makeup increases susceptibility to immune depletion and impaired immune reconstitution, the authors provide novel tools for prognosticating not only the development of AIDS but those who might benefit from earlier initiation of HAART,” he said.

Carl Dieffenbach, Ph.D., director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID), said, “The observation that CCL3L1-CCR5 genetic makeup has its greatest impact on immune recovery when persons were started on therapy with CD4+ counts of less than 350 cells/mm3 underscores the importance of starting persons on therapy earlier than later.”

Anthony Fauci, M.D., director of the NIAID, which helped finance the study, called these results “a major breakthrough in our understanding of how genes affect disease course and HIV-1 treatment response.” He said the authors effectively showed that other genetic variations, such as HLA alleles, that play such a key role in minimizing immune depletion during HIV infection may not have as major an impact on immune reconstitution during therapy.

The study suggests the need for new thinking in HIV-1 management. “The current debate about when to initiate antiretroviral therapy might need to be redirected toward first assessing who should be considered for therapy, on the basis of the host genetic endowment,” Dr. Ahuja said.

Joel Kupersmith, M.D., chief research and development officer for the Veterans Health Administration, said, “Dr. Ahuja’s groundbreaking research is in line with the VA’s mission for providing personalized medicine for veterans. We look forward to the translation of these findings into improved care for HIV-infected veterans and HIV patients worldwide.” The Veterans Health Administration is part of the U.S. Veterans Administration.

The CD4+ restoration was more closely associated with number of copies of CCL3L1 than with CCR5 status. “This suggests that drugs that mimic or amplify the activity of CCL3L1 may be very effective,” Dr. Dolan said.”

The IDCRP capitalizes on resources centered at USU and the NIH as well as the distributed network of DoD Military Treatment Facilities, thus creating a unique infectious disease clinical research network. The collaborative relationship between the DoD and NIAID draws on the strengths of both agencies. In addition to its expertise in infectious disease research, NIAID brings extensive experience in education, biostatistics, and clinical trials monitoring.

USU, located in Bethesda, Maryland, on the grounds of the National Naval Medical Center, is a traditional U.S. academic health center with a unique emphasis on educating the next generation of health care providers and researchers in military medicine, humanitarian efforts as well as responses to disasters, emerging infectious diseases, and other public health emergencies.

Acknowledgements: Sunil K. Ahuja1-3, Hemant Kulkarni1,2,13, Gabriel Catano1,2,13, Brian K. Agan4-7,13, Jose F. Camargo1,2, Weijing He1,2, Robert J. O’Connell4,5, Vincent C. Marconi4,5,7, Judith Delmar4,5,7, Joseph Eron8, Robert A. Clark1,2, Simon Frost9,10, Jeffrey Martin11, Seema S. Ahuja1,2, Steven G. Deeks12, Susan Little9, Douglas Richman9,10, Frederick M. Hecht12 & Matthew J. Dolan4-7.

1Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, Texas. 2Department of Medicine, The University of Texas Health Science Center at San Antonio. 3Departments of Microbiology & Immunology and Biochemistry, UT Health Science Center San Antonio. 4Infectious Disease Clinical Research Program, Uniformed Services University, Bethesda, Md. 5Infectious Diseases Service and 6Henry M. Jackson Foundation, Wilford Hall Medical Center (U.S. Air Force), San Antonio, Texas. 7San Antonio Military Medical Center (formerly Brooke Army Medical Center). 8University of North Carolina. 9Antiviral Research Center, Department of Medicine, University of California, San Diego. 10Veterans Affairs San Diego Health Care System. 11Department of Epidemiology and Biostatistics, University of California, San Francisco. 12Department of Medicine, San Francisco General Hospital. 13These authors contributed equally to this work.”
(dated and note from University of Texas Health Science Center, San Antonio)

Source: Uniformed Services University of the Health Sciences (USU)

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