Receptors, co-receptors and immunity to HIV

A single HIV particle is called a virion. Its core, called the capsid, contains two single strands of HIV RNA. The core is surrounded by a protective lipid bilayer and this shell is called the viral envelope. Enmeshed in the viral envelope is a complex HIV protein called env. Two glycoproteins make up env and these protrude from the virion. The cap of the protein is called gp120 and the stem is gp41. For HIV to enter a host cell, it must first use gp120 to attach to a CD4 receptor.

The CD4 receptor is found on CD4 T-cells and macrophages. The host cell has neutralising antibodies that can block gp120’s attachment, but because HIV is a new virus, there is some lag time in producing enough antibodies to prevent this. Additionally, after gp120 successfully attaches to the CD4 cell, it can change shape to avoid recognition by the CD4 cell’s neutralising antibodies, a process known as conformational masking. The conformational change in gp120 allows it to bind to a second receptor on the CD4 cell surface.

The second docking area on the CD4 cell surface is a chemokine receptor and there are two possibilities, CCR5 or CXCR4. The viral preference for using one co-receptor versus another is called 'viral tropism'. Chemokine receptor 5 (CCR5), is used by macrophage-tropic (M-tropic) HIV to bind to a cell. About 90% of all HIV infections involve the M-tropic HIV strain. CXCR4, also called fusin, is a glycoprotein-linked chemokine receptor used by T-tropic HIV (ones that preferentially infect CD4 T-cells) to attach to the host cell.

Once the HIV envelope has attached to the CD4 molecule and is bound to a chemokine co-receptor, the HIV envelope utilises a structural change in the gp41 envelope protein to fuse with the cell membrane. The HIV virion is then able to penetrate the CD4 membrane. Once within a cell, virus is safe from attack by antibodies, but vulnerable to attack by CD8 cells (cytotoxic T-lymphocytes or CTLs). 


Macrophage (M-tropic) strains of HIV-1 use the β-chemokine receptor CCR5 for binding and are able to infect macrophages, dendritic cells, and CD4 T-cells. Almost all HIV-1 isolates are successfully transmitted using the CCR5 co-receptor. M-tropic HIV replicates in peripheral blood lymphocytes and does not form syncytia. Syncytia are 'giant cells', multicellular clumps that have been formed by fusing with other cells. Non-syncytia-inducing (NSI) strains of virus are considered less virulent than those that do form syncytia.

Some people have a 32-base pair deletion (delta 32) in the gene that encodes the CCR5 receptor. If they receive this deletion from both parents, they are said to be homozygous for CCR5-delta32. This deletion is highly protective because the receptor is faulty and HIV cannot use it to enter the cell.

There have been a few cases in which someone homozygous for the deletion was infected with dual-tropic HIV and suffered rapid depletion of CD4 T-cells. This is the exception. Ordinarily, it is a great advantage to have this deletion. If someone inherits the deletion from just one parent, they are said to be heterozygous for CCR5 and this can slow HIV progression. The prevalence of 32-base pair deletion is estimated to be as high as 10 to 15% in Caucasians, but only around 2% in African Americans and almost non-existent in native Africans and East Asians.

Other mutations in CCR5 that effect disease progression have also been identified, including some that might play a protective role in HIV acquisition or progression in non-Caucasian people.1 Slower disease progression is also associated with high levels of the CCR5 59353-C polymorphism in the promoter DNA that controls the amount of CCR5 that cells produce.2

Variations also occur in the amount of chemokines in people’s blood. Chemokines compete with HIV for chemokine receptors, preventing HIV from using the receptors and reducing the susceptibility of cells to infection. Unusually high levels of the CCR5-using chemokines RANTES, MIP-1 alpha, and MIP-1 beta are seen in long-term non-progressors, as well as in exposed seronegative individuals (people with repeated exposure to the virus through unprotected sex who do not become infected).


CXCR4, also known as fusin or X4, is the receptor used by T-tropic strains of HIV. T-tropic HIV attaches first to the CD4 receptor and then to the α-chemokine receptor CXCR4. T-tropic HIV can be syncytium-inducing (SI) and the presence of SI-inducing variants of HIV has been correlated with rapid disease progression in HIV-positive individuals. 

CXCR4-tropic HIV strains tend to emerge in the body during the course of HIV infection. People whose virus uses the CXCR4 co-receptor tend to have higher viral loads and much lower CD4 cell counts. Studies suggest that the presence of the CXCR4-using strain does not affect the outcome of antiretroviral therapy.3 4 

X4 virus increases the risk of disease progression. When found in baseline plasma, it is an independent predictor of poor immunological response and mortality.5 6

As with CCR5, a proportion of the population has a genetic mutation that impairs the efficiency or ability of T-tropic virus to attach. Around 1% of Caucasians do not produce this co-receptor, reducing their susceptibility to CXCR4-tropic strains of HIV.

Researchers are puzzled about why it takes CXCR4-tropic HIV so long to emerge in an infected individual. It has been postulated that there is an unknown selective pressure against the emergence of CXCR4 during early infection. One theory is that the degradation of lymphoid tissue disrupts the natural ligand of CXCR4.4 

Dual and mixed-tropic HIV

M-tropic and T-tropic strains of HIV coexist in the body. At some point in infection, gp120 is able to attach to either CCR5 or CXCR4. This is called dual tropic virus or R5X4 HIV. Virus that can utilise the CXCR4 receptor on both macrophages and T-cells is also termed dual-tropic X4 HIV.7  Mixed tropism results when an individual has two virus populations; one using CCR5 and the other CXCR4 to bind to the CD4 T-cell.

Generally, CCR5 is expressed by memory CD4 T-cells and CXCR4 is expressed by naive CD4 T-cells. In a healthy immune system, memory cells divide at much higher rates (approximately tenfold) than naive CD4 T-cells. CXCR4-tropic virus is probably disadvantaged during early infection when there is a great abundance of memory CD4 T-cells present. With disease progression, naive cell division is more approximate to that of memory cells and there tends to be a shift in tropism from CCR5 to CXCR4. This would imply that the emergence of CXCR4-using virus is both a cause and a consequence of immunodeficiency.4

Testing for tropism

Attachment inhibitors are designed to block HIV chemokine co-receptors. Maraviroc (Celsentri/Selzentry), the first approved CCR5 antagonist was approved in 2007. Even a very low amount of CXCR4-tropic virus present when a person starts CCR5 inhibitor therapy could cause viral breakthrough.8  For this reason, a tropism test is required before starting therapy with maraviroc.

Recent studies also indicate that disease progression may occur much faster in ARV-naive patients with D/M-tropic virus than in patients with R5-tropic virus, indicating a role for tropism testing in making clinical decisions regarding the timing of therapy.9

For more information, see Viral phenotype in the section on Factors affecting disease progression below as well as Entry inhibitors in Ways of attacking HIV.

Other chemokine-related mutations

Various polymorphisms in the genes for other chemokine receptors have also been investigated for their potential influence on the progression of HIV disease. A number of studies have identified an association between the CCR2B-64I mutation in the CCR2 gene and slower disease progression, as well as long-term non-progressor status.2 As was found with the CCR5 mutation, disease progression among injecting drug users was not affected.6

Mutation 280 in the CX3CR1 receptor has been linked to faster HIV disease progression and the I/I249 mutation in CX3CR1 may be associated with more rapid disease progression in children.10 11  

Polymorphisms in the genes of chemokines also affect HIV disease progression. The SDF-1-3A mutation in the chemokine stromal derived factor 1 (SDF-1) has been associated with reduced and increased risk of disease progression in different studies.2 12 13 

CCL3L1 (MIP-1alphaP) is a potent HIV-suppressive chemokine and ligand for the HIV co-receptor CCR5. Having a CCL3L1 copy number lower than the population average may increase susceptibility to HIV and increase disease progression following infection.14

Only a small proportion of long-term non-progressors are explained by co-receptor polymorphisms. About 60% of non-progressors have normal CCR5 genes and 80% have normal CCR2 genes. It is likely that a number of host and viral factors combine to determine rates of disease progression.


  1. Capoulade-Métay C et al. New CCR5 variants associated with reduced HIV coreceptor function in southeast Asia. AIDS 18: 2243-2252, 2004
  2. Easterbrook PJ et al. Chemokine receptor polymorphisms and human immunodeficiency virus disease progression. J Infect Dis 180: 1096-1105, 1999
  3. Brumme Z et al. Influence of polymorphisms within the CXCR1 and MDR-1 genes on initial antiretroviral therapy response. AIDS 17: 201-208, 2003
  4. Ribeiro RM et al. Naive and memory cell turnover as drivers of CCR5-to-CXCR4 tropism switch in Human Immunodeficiency Virus Type 1: implications for therapy. J Virol 80: 802-809, 2006
  5. Brumme ZL et al. Molecular and clinical epidemiology of CXCR4-using HIV-1 in a large population of antiretroviral-naive individuals. J infect Dis 192: 466-474, 2005
  6. Moyle G et al. Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection. J Infect Dis 191: 866-872, 2005
  7. Yanjie Y et al. Role of CXCR4 in cell-cell fusion and infection of monocyte-derived macrophages by primary human immunodeficiency virus type 1 (HIV-1) strains: two distinct mechanisms of HIV-1 dual tropism. J Virol 73: 7117-7125, 1999
  8. Lalezari J et al. 873140, a novel CCR5 antagonist: antiviral activity and safety during short-term monotherapy in HIV-infected adults. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, abstract H-1137b, 2004
  9. Waters L et al. The impact of HIV tropism on decreases in CD4 cell count, clinical progression, and subsequent response to first antiretroviral therapy regimen. Clin Infect Dis 46: 1617-1623, 2008
  10. Schinkel J et al. No evidence of an effect of the CCR6 delta32/+ and CCR2b 64I/+ mutations on HIV-1 disease progression among HIV-1-infected injecting drug users. J Infect Dis 179: 825-831, 1999
  11. Faure S et al. Deleterious genetic influence of CX3CR1 genotypes on HIV-1 disease progression. J Acquir Immune Defic Syndr 32: 335-337, 2003
  12. Singh K et al. Polymorphisms in the gene encoding for CX3CR1 are important determinants of HIV-1-related disease progression of children. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 153, 2004
  13. Winkler C et al. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. Science 279: 387-391, 1998
  14. Gonzalez E et al. The influence of CCL3L1 gene-containing segmental duplications on HIV/AIDS susceptibility. Science 307: 1434-1440, 2005
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

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