Fisher.qxp 28/1/08 2:54 pm Page 62
HIV and AIDS CCR-5 Virus
HIV Tropism – Variations and Consistency
a report by
Zoe Warwick and Martin Fisher
Department of Genito-urinary Medicine, Royal Sussex County Hospital
HIV Infection is able to use either the CCR-5 or CXCR-4 co-receptor, although dual-tropic
The first stage of the HIV life-cycle is that of viral entry into CD4-positive viruses may use one co-receptor more efficiently than the other. Often, both
cells. This process relies on a series of sequential interactions between viral R5 and X4 viruses can be present in an HIV-infected individual. The viral
surface glycoproteins (gps) and CD4 cell surface receptors.
1
GP160 is made population is then described as being mixed-tropic. Currently, routine assays
up of two subunits, gp120 and gp41. Gp120 binds to the CD4 receptor on used to determine viral tropism are unable to differentiate between dual- and
the cell surface, triggering conformational change in gp120. These changes mixed-tropic viruses, so the term dual/mixed (D/M) is applied. The 35 amino
expose a hydrophobic binding site (V3 loop) of gp120 that allows binding acid V3 loop of gp120 appears to be particularly important in determining
of gp120 to a seven-transmembrane co-receptor on the cell surface. virus tropism, cytopathicity and infectivity.
7
Generally, CXCR-4-using viruses
Different HIV strains use either (or both) chemokine (C-C motif) receptor 5 carry positively charged amino acids at positions 11 and/or 25 in the V3 loop
(CCR-5) or chemokine (C-X-C motif) receptor 4 (CXCR-4) as co-receptors (the ‘11/25 genoptype’), while CCR-5-tropic viruses do not.
8,9
and are therefore described as R5 or X4 viruses (CCR-5-tropic or CXCR-4-
tropic) or mixed/dual-tropic. These co-receptors were identified following It was found that individuals homozygous for a defective CCR-5 gene
studies with chemokine signalling molecules that were shown to block HIV- (CCR-5 Delta32) were essentially immune to HIV-1 infection.
10
The 32-base
1 infection.
2–4
Co-receptor binding enables gp41 to insert a fusion peptide pair deletion results in a frameshift mutation such that CCR-5 molecules
into the target cell membrane, bringing the viral and cell membranes into cannot be expressed on the cell surface. Heterozygous individuals have
close proximity and resulting in fusion and entry of the viral core into the reduced cell surface expression of CCR-5 and can be infected with HIV, but
target cell. Once within the target cell, reverse transcription of viral RNA appear to have a delayed CD4 count decline and reduced HIV disease
occurs and the resulting DNA is spliced into the host genome. On activation progression.
11
R5-tropic viruses are responsible for the majority of sexually
the infected cell transcribes the complete viral genome, resulting in the transmitted cases of HIV, even when CXCR-4 virus is present in the donor.
production of immature viral particles. Acquisition of HIV via CXCR-4 virus has occurred, but is thought to be
rare.
12,13
Spermatozoa may selectively carry R5 HIV as they possess both
Tropism CCR-3 and CCR-5 but not CXCR-4 on their surface.
14
There also appears to
Tropism refers to the co-receptor that a particular HIV strain uses to mediate be specific sequestration of X4 strains by genital epithelial cells, which could
entry into the CD4-positive cell. HIV utilising the CCR-5 co-receptor, but explain in part the HIV tropism selection process during sexual intercourse.
15
not CXCR-4, is described as being a CCR-5-tropic virus. Similarly, HIV using R5 virus is the predominant virus during early infection, while X4 (or D/M
the CXCR-4 co-receptor is described a CXCR-4-tropic virus. While around a tropic) virus is seen more frequently in advanced infection and is associated
dozen other chemokine receptors have been shown in vitro to act as a with a more rapid loss of CD4+ T cells and disease progression,
16
although it
co-receptor for HIV-1, there is currently little evidence that the virus uses them remains unclear whether this is ‘cause’ or ‘effect’. Of treatment-naïve
in vivo. GPR-15 (also known as Bob) and CXCR-6 (Bonzo) are two patients, 81–88% have the R5 virus, with fewer than 1% harbouring only
co-receptors that have both been identified in this manner, but they are more X4.
17,18
Co-receptor tropism does not seem to affect response to HAART.
19
In
commonly used by the simian immunodeficieny virus (SIV).
5
HIV-2 appears to patients infected with subtype B HIV-1, there is often a co-receptor switch in
use a broader range of co-receptors than HIV-1, including Bob, Bonzo, late-stage disease and T-tropic variants appear that can infect a variety of
chemokine (C-C motif) receptor 1 (CCR-1), chemokine (C-C motif) receptor T cells through CXCR-4.
20,21
Around 50% of AIDS patients carry X4. It is
2b (CCR-2b) and chemokine (C-C motif) receptor 3 (CCR-3),
6
although as the unclear whether X4 variants are inherently more pathogenic and directly
asymptomatic stage of infection with HIV-2 has lower viral loads, isolates can responsible for more rapid disease progression or whether X4 virus emerges
be difficult to culture. The term ‘dual tropism’ is applied to a virus strain that as a consequence of CD4 depletion and increasing immune suppression.
22
Zoe Warwick is a Specialist Registrar at Brighton and Sussex University Hospitals NHS Trusts.
Measuring Tropism
She is a member of the Royal College of Physicians (RCP). Dr Warrick gained her BSc in Currently, the only licensed method for determining HIV-1 tropism is the
biomedical sciences in 1992 and qualified as an MB, BS from Kings College, London, in 1995.
Trofile™ assay (Monogram Biosciences, US).
23
The assay has a lower limit of
She obtained her diploma in tropical medicine and hygiene in 1999.
detection, detecting the presence of X4 virus 83% of the time when it
Martin Fisher is a Consultant in HIV/Genito-urinary Medicine at Brighton and Sussex University
comprises at least 5% of the total viral population, and sensitivity varies with
Hospitals NHS Trust. He has published widely and actively researches antiretroviral therapy,
viral load (see Table 1). Phenotypic expression of Delta32 in homozygous
treatment strategies for HIV infection and transmission of HIV and other sexually transmitted
infections. Dr Fisher graduated from Guy’s Hospital in London and subsequently trained in
individuals does not have any apparent detrimental consequences to health,
HIV/Genito-urinary Medicine at the Chelsea and Westminster and St Mary’s hospitals. suggesting that artificially inhibiting CCR-5 should not result in significant
E:
martin.fisher@bsuh.nhs.uk
toxicity. An increase in the frequency and severity of West Nile Virus
infection has been reported,
24
but is unlikely to have a significant impact on
62 © TOUCH BRIEFINGS 2007
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