Printer Friendly

Mutant Chemokine Receptor (CCR-5) and Its Relevance to HIV Infection in Arabs.

To the Editor: Approximately 10% of HIV-infected patients may remain AIDS-free for a long time; moreover, some persons do not become infected with HIV despite multiple high-risk sexual exposures (1.2). Factors responsible for this relative resistance to infection and disease include cytotoxic T cells, neutralizing antibodies, high concentrations of certain chemokines (e.g., RANTES, MIP-1), human leukocyte antigen haplotype, mannose-binding protein, and tumor necrosis factor alpha, C4, and TAP polymorphism (2-4). One of the chemokine receptors, CCR-5, which along with CD4 acts as co-receptor for HIV entry into macrophages, provides upon mutation a genetic restriction to HIV infection in homozygous persons and control of disease progression in heterozygous persons (5.6). Thus a 32bp deletion in the open reading frame of the region encoding the second extracellular loop of this receptor causes synthesis of a highly truncated protein that fails to express on the cell surface, leading to loss of HIV-1 co-receptor activity.

Studies in healthy Caucasian Europeans and North Americans show that approximately 1% of the population are homozygous for this deletion (D32), whereas 15% to 20% are heterozygous (5-t)); surprisingly, a higher percentage (up to 20%) of persons at high risk for HIV but HIV-negative are homozygous for this deletion. However, no such mutation is seen in Japanese, Native Americans, Chinese, Africans, and Tamil Indians, which suggests that in these groups either resistance to HIV infection is not present or factors other than mutated CCR-5 are in operation. African-Americans and Hispanics show a low rate of mutation, possibly because of intermarriage with Caucasians (4). The low frequency of CCR-5 mutation in Arabs with close contacts with Turks in the Eastern Province of Saudi Arabia may also be due to intermarriage. However, certain persons with mutated CCR-5 can become HIV-infected (10); in such cases other chemokine receptors (e.g., CXCR-4, CCR-2, and CCR-3) are believed to facilitate infection.

HIV infection in Saudi Arabia (population 18 million) is uncommon; the World Health Organization has so far (1985 to 1997) documented 334 cases of AIDS in this region (11). We, therefore, studied for the first time the mutation of CCR-5 in Arabs residing in Saudi Arabia. DNA was isolated from the peripheral blood mononuclear cells of 105 male blood donors not infected with HIV and nine HIV-infected patients (seven male and two female). The latter were divided into three groups, according to published criteria (2): four persons whose infection did not progress over the long term and who showed only modest decline of CD4 count after several years of infection, one person whose infection progressed normally, and four persons whose infection progressed rapidly and CD4 count fell below 100/[micro]l within 2 years. Primers flanking 32 nucleotide deletion of CCR-5 were used to generate wild type (W) and deleted (D32) fragments of 189 bp and 157 bp, respectively (5). Amplification was done in a Perkin-Elmer thermal cycler 9,600, by a 20 [micro]l reaction mixture that contained 0.25mM of dNTPs, 20 pM of each primer ('5-CAAAAAGAAGGTCTTCATTACACC-3, 5-CCTGTGCCTCTTCTTCTCATTTCG-3'), and 0.5 units of Taq polymerase in l x reaction buffer. All reagents were obtained from Pharmacia (Sweden). The amplified product was separated on 2% agarose at 120 V for 45 min and examined under UV light. Of the uninfected blood donors, 104 (99%) were homozygous for the wild type, and 1 (0.96) was heterozygous for the mutation. None of the HIV-infected patients had the mutation. Thus, the mutation is present, albeit infrequently, in Arabs. A review of 68 HIV-infected patients in our files showed that, as in Caucasians, infection progressed rapidly in 8%, did not progress over the long term in 6%, and progressed normally in 86% (2). Therefore, other hitherto unknown protective factors must be operative in Arabs.


(1.) Malkovsky M. HLA and natural history of HIV infection. Lancet 1996;348:142-3.

(2.) Haynes BF, Pantaleo G, Fauci AS. Toward an understanding of the correlates of protective imnmnity to HIV infection. Science 1996;271:324-8.

(3.) Cocchi F, DeVico AL, Garzine-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1a and MIP-1b as the major HIV suppressive factors produced by CD8+ Tcells. Science 1995;270:1811-5.

(4.) McNicholl JM, Smith DK, Qari SH, Hodge T. Host genes and HIV: the role of the chemokine receptor gene CCR-5 and its alleles (32 CCR-5). Emerg Infect Dis 1997:3:261-71.

(5.) Huang VY, Paxton WA, Wollinsky SM, Neumann AU, Zhang L, He T, et al. The role of mutant CCR-5 allele in HIV-1 transmission and disease progression. Nature Med 1996;2:1240-3.

(6.) Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, et al. Genetic resistance of HIV infection and progression to AIDS by deletion of the CKR5 structural gene. Science 1996;273:1856-62.

(7.) Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, et al. Homozygous defect in HIV co-receptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996;86:367-77.

(8.) Samson M, Libert F, Duranz B J, Rucker J, Liesnard C, Farber CM, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996;382:722-5.

(9.) Zimmerman PA, Bucklewhite A, Alkhatib G, Spalding T, Kubofcik J, Combadiere C. Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5- studies in populations with quantified risk. Mol Med 1997;3:23-36.

(10.) O'Brien TR, Winkler C, Dean M, Nelson, JAE, Carrington M, Michael NL, et al. HIV-1 infection in man homozygous for CCR-5 D32. Lancet 1997;349:1219-20.

(11.) World Health Organization. AIDS update: reported AIDS cases in East Mediterranean Region. EMR AIDS News 1997;1:8.

Iman H. Al-Sheikh, Amjad Rahi, and Mohammed Al-Khalifa King Faisal University and Regional Laboratory, Ministry of Health, Dammam, Saudi Arabia
COPYRIGHT 1999 U.S. National Center for Infectious Diseases
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 1999, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

Article Details
Printer friendly Cite/link Email Feedback
Author:Al-Khalifa, Mohammed
Publication:Emerging Infectious Diseases
Geographic Code:0JINT
Date:Jan 1, 1999
Previous Article:New emm (M Protein Gene) Sequences of Group A Streptococci Isolated from Malaysian Patients.
Next Article:Meeting Summaries.

Related Articles
Finding a partner for fusin at last.
The mutant genes that stymie HIV.
Mutated gene can delay onset of AIDS.
Inner strength: gene therapy aims to build cells that thwart HIV replication.
HIV sexual spread exploits immune sentinels.
Katy, bar the door! HIV entry inhibitors.
Long-term nonprogressors: the study of HIV infection without progression to AIDS.
Arteries may be vulnerable to HIV attack.
HIV prevalence in a gold mining camp in the Amazon region, Guyana. (Dispatches).
HIV-1 Env-chemokine receptor interactions in primary human macrophages: entry and beyond.

Terms of use | Copyright © 2018 Farlex, Inc. | Feedback | For webmasters