Small Molecule Blocks Cell-Surface Receptor Needed For HIV-1 Infection Of T Cells: New Generation Of Combination Therapies Suggested

October 20, 1997

In May and June of last year, scientists discovered several new receptors on the surface of immune-system cells that are required -- along with the long-known CD4 receptor -- for HIV-1 to enter and infect those cells. Now, little more than a year later, researchers at the University of Pennsylvania Medical Center and the University of Texas Medical Branch at Galveston have identified a small molecule that blocks one of these so-called coreceptors, preventing infection by a number of the HIV strains that target T cells. These strains of the virus are associated with progression from relatively asymptomatic HIV infection to the disease AIDS.

The discovery suggests that novel combination therapies that inhibit the full set of coreceptors could well prove effective in preventing or treating HIV infection and AIDS. The findings are reported in the October 20 Journal of Experimental Medicine. Two additional papers announcing similar results appear in the same issue.

"The importance of these studies is that they provide proof of principle," says coauthor Robert W. Doms, MD, PhD, an assistant professor of pathology and laboratory medicine at Penn in whose laboratory many of the experiments were conducted. "They show that we can develop small molecules to inhibit these newly identified coreceptors that HIV absolutely needs to get into cells, thus preventing infection."

The inhibitory molecule investigated in the study is a small peptide called ALX40-4C, the anti-HIV activity of which was first noted last year by senior author William A. O'Brien, PhD, at Galveston. Lead author Benjamin J. Doranz, BA, a researcher in Doms' laboratory, performed experiments indicating that ALX40-4C operated by blocking one of the coreceptors, CXCR4, which is used by the strains of HIV that infect T cells in the later stages of disease progression, known as T-tropic viruses. Another coreceptor, CCR5, is used by viral strains that show a predilection for macrophages in the earliest stages of infection, referred to as M-tropic viruses. Over time, in an infected person, viruses evolve from using CCR5 to using CXCR4, from M-tropic to T-tropic.

In one set of experiments, seven of ten strains of HIV isolated from patients by O'Brien used the CXCR4 coreceptor, and three of these relied on CXCR4 sufficiently to be blocked by ALX40-4C.

"One or more small molecules like this might delay or prevent evolution of the virus from using CCR5 to using CXCR4," Doms says, noting that it is the viral strains that use CXCR4 that correlate with dropping T-cell counts and progression to AIDS. "We also hope to develop small-molecule inhibitors of CCR5, the receptor used by viruses that start an infection. To be fully effective in countering HIV, we might need a cocktail that included a small-molecule inhibitor of CCR5 in conjunction with one against CXCR4."

In addition to Doranz and Doms, the third Penn-based coauthor is Matthew P. Sharron, BA. Other coauthors on the paper include Kathie Grovit-Ferbasi, Si-Hua Mao, and Matthew B. Goetz at the West Los Angeles Veterans Affairs Medical Center and the University of California at Los Angeles School of Medicine. Eric S. Daar with the Cedars-Sinai Medical Center and the UCLA School of Medicine is also a coauthor. ALX40-4C is manufactured by Allelix Inc., Mississauga, Ontario, Canada.

Grant funding for this work was provided by the National Institutes of Health. Doranz was supported by a predoctoral fellowship from the Howard Hughes Medical Institute.

The University of Pennsylvania Medical Center's sponsored research ranks fifth in the United States, based on grant support from the National Institutes of Health, the primary funder of biomedical research in the nation -- $149 million in federal fiscal year 1996. In addition, for the second consecutive year, the institution posted the highest growth rate in its research activity -- 9.1 percent -- of the top ten U.S. academic medical centers during the same period. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page (http://www.med.upenn.edu) and to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science.

###


University of Pennsylvania School of Medicine

Related HIV Articles from Brightsurf:

BEAT-HIV Delaney collaboratory issues recommendations measuring persistent HIV reservoirs
Spearheaded by Wistar scientists, top worldwide HIV researchers from the BEAT-HIV Martin Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy (BEAT-HIV Collaboratory) compiled the first comprehensive set of recommendations on how to best measure the size of persistent HIV reservoirs during cure-directed clinical studies.

The Lancet HIV: Study suggests a second patient has been cured of HIV
A study of the second HIV patient to undergo successful stem cell transplantation from donors with a HIV-resistant gene, finds that there was no active viral infection in the patient's blood 30 months after they stopped anti-retroviral therapy, according to a case report published in The Lancet HIV journal and presented at CROI (Conference on Retroviruses and Opportunistic Infections).

Children with HIV score below HIV-negative peers in cognitive, motor function tests
Children who acquired HIV in utero or during birth or breastfeeding did not perform as well as their peers who do not have HIV on tests measuring cognitive ability, motor function and attention, according to a report published online today in Clinical Infectious Diseases.

Efforts to end the HIV epidemic must not ignore people already living with HIV
Efforts to prevent new HIV transmissions in the US must be accompanied by addressing HIV-associated comorbidities to improve the health of people already living with HIV, NIH experts assert in the third of a series of JAMA commentaries.

The Lancet HIV: Severe anti-LGBT legislations associated with lower testing and awareness of HIV in African countries
This first systematic review to investigate HIV testing, treatment and viral suppression in men who have sex with men in Africa finds that among the most recent studies (conducted after 2011) only half of men have been tested for HIV in the past 12 months.

The Lancet HIV: Tenfold increase in number of adolescents on HIV treatment in South Africa since 2010, but many still untreated
A new study of more than 700,000 one to 19-year olds being treated for HIV infection suggests a ten-fold increase in the number of adolescents aged 15 to 19 receiving HIV treatment in South Africa, according to results published in The Lancet HIV journal.

Starting HIV treatment in ERs may be key to ending HIV spread worldwide
In a follow-up study conducted in South Africa, Johns Hopkins Medicine researchers say they have evidence that hospital emergency departments (EDs) worldwide may be key strategic settings for curbing the spread of HIV infections in hard-to-reach populations if the EDs jump-start treatment and case management as well as diagnosis of the disease.

NIH HIV experts prioritize research to achieve sustained ART-free HIV remission
Achieving sustained remission of HIV without life-long antiretroviral therapy (ART) is a top HIV research priority, according to a new commentary in JAMA by experts at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The Lancet HIV: PrEP implementation is associated with a rapid decline in new HIV infections
Study from Australia is the first to evaluate a population-level roll-out of pre-exposure prophylaxis (PrEP) in men who have sex with men.

Researchers date 'hibernating' HIV strains, advancing BC's leadership in HIV cure research
Researchers have developed a novel way for dating 'hibernating' HIV strains, in an advancement for HIV cure research.

Read More: HIV News and HIV Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.