Scientific discoveries have revealed new and important
information on how the HIV virus is able to infect different types of human
cell. This is resulting in new ideas which will inform future thinking about
possible therapeutic intervention in HIV-infected individuals. In future,
this might well involve a two-pronged approach incorporating both an attack
on the virus itself and therapeutic immunomodulation to prevent the decline
of the immune system.
Chemokines:
Immune cell trafficking (above) is controlled by two components:
Adhesion molecules
Chemoattractant cytokines (chemokines) and their receptors:
3 classes: C (1), C-C (beta), C-X-C (alpha)
characteristic cysteine (C-C) bridge or C-X-C amino acid repeat
Information about the identity of the HIV receptor has been revealed by several
studies:
The fact that CD4 is a component of the HIV receptor has been known since
1984, also that CD4 on its own is not sufficient to allow HIV to infect cells.
Cocchi et al
(Science
270: 1811,1995): the CC chemokines RANTES, MIP1-α and MIP-1-β block infection of lymphocytes with
macrophage-tropic HIV isolates by interacting with the CCR5 receptor.
Feng et al
(Science
272: 872, 1996): CXCR4 ligand blocks infection with lymphocyte-tropic
HIV isolates.
(N.B. Some HIV isolates use CCR-3; some HIV isolates can use more than 1
CCR; pattern of use does not fall into neat categories).
Dean M. et al (Science 273: 1857, 1996) studied 1,955 men either infected with HIV or at high risk for HIV infection:
Most people have two normal alleles for the CCR5 gene.
1:7 have one mutant allele (32bp deletion "Delta32")
and one normal allele (heterozygous).
1:100 have two mutant alleles.
Mutant allele has a frequency of 11% among Caucasians, 1.7% among African
Americans, less than 1% in Asian populations.
17/612 (less than 3%) of people at high risk for HIV infection had two copies
of the mutant CCR5 gene.
NONE of 1,343 HIV-infected people had the mutation.
Heterozygous genotype occurred in 15% of HIV-infected subjects, 14% of subjects
not infected with HIV - one mutant copy of the gene does not protect from
HIV infection
BUT the average time to AIDS for all HIV-infected men in the study
was 10 years, heterozygous men progressed to AIDS in an average of 13 years.
The observation that CCR5 mutations can protect against HIV infection strongly
suggests that CCR5 plays a critical role early in HIV infection since infection
can be blocked if this receptor is not present. At later stages of infection,
other co-receptors such as CXCR4 may take over this role as the properties of
the virus population in a patient changes. However, this is only a theory at
present and more work is needed to confirm this idea.
Isolates that use CCR5 but not CXCR4 should be termed R5 viruses
Isolates that use CXCR4 but not CCR5 should be termed X4 viruses
Isolates able to use CCR5 and CXCR4 should be termed R5X4 viruses
Under this scheme, R5 viruses are the most common sexually-transmitted isolates.
In an infected individual, these eventually evolve into R5X4 and/or X4 viruses. Such
an understanding of HIV infection can explain many features of the biology of AIDS,
e.g:
Influenza virus enhances CXCR4-dependent HIV-1 infection:
Influenza infection results in an increase in the susceptibility
of cells to infection by HIV-1 isolates that use the CXCR4 coreceptor.
Since optimal HIV infection
requires activated CD4+ lymphocytes, it is conceivable that any event that
results in increased immune activation increases the number of potential
HIV
target cells and hence may indirectly accelerate virus spread. Alternatively,
coinfecting agents may directly alter the susceptibility of target cells
to
HIV infection, and any agent that triggers increased coreceptor expression
could be viewed as a potential accelerator of HIV pathogenesis.
Syphilis increases HIV-1 risk by inducing CCR5 expression: Either T.
pallidum,
a representative treponemal lipoprotein, or a corresponding synthetic lipopeptide
induced CCR5 on CD14 monocytes but not on CD3 lymphocytes. In contrast, T.
pallidum or its components did not induce CXCR4, the coreceptor
for T cell-tropic strains of HIV-1. Consistent with these findings, T.
pallidum,
lipoprotein, and synthetic lipopeptide all promoted the entry of a macrophage-tropic,
but not a T cell-tropic, strain of HIV-1 into monocytes.
Concentrations of chemokines used to block HIV replication in vitro are
10-100 greater than the levels at which they are produced in the body.
Chemokines induce potent inflammation, hence derivatives will need
to be used.
Functional deletion of the CCR5 receptor by intracellular immunization
produces cells that are refractory to CCR5-dependent HIV-1 infection and
cell fusion.
Steinberger
P, et al. PNAS USA 2000, 97: 805-810.
