Comment Re:Not really news (Score 1) 723
"the case of David Crohn [pbs.org] and others who lack secondary CCR5 (for macrophages) or CXCR4 (for T-cells) receptors and are thus resistant to HIV infection. NB: CCR5 and CXCR4 are believed to be secondary to the CD4 receptor, found on both cell types, in the HIV binding process."
You are precisely right in mentioning the chemokine coreceptors.
CCR5 is the coreceptor (in fact, it has been _inconclusively_ demonstrated that CD4 may NOT be totally necessary to mediate viral entry of some strains into the cell, but the chemokine "co"receptors, that is CXCR4 or CCR5, absolutely are) which is present on the cell membrane of Macrophages, among other cell types. Macrophages are almost universally the first cell type infected in an HIV patient, regardles of whether the exposure route was sexual or by blood-blood contact.
This "immunity" against HIV infection so far as I know involves a truncated CCR5 gene, but NOT necessarily a truncated CXCR4 gene (as was previously assumed). The consequences of this are that the individual is simply NOT Immune to HIV infection in any normal sense of the word, but is for all intents and purposes incapable of *contracting* HIV in the first place through the normal routes unless Th (helper-T cells, typically CD4+) cells are directly exposed to HIV virus, something that would probably happen only if HIV were directly injected into the lymph.
Since Th cells do not possess CCR5, but rather CXCR4 which is not affected by the CCR5 mutation, T-tropic HIV strains could theoretically infect any individual with a mutated or nonexistant CCR5 gene assuming CXCR4 is not affected, which it is usually not. If the virus could get to the T-cells that is. Since they do not patrol the periphery, let alone extravasate out of capillaries into tissue, this is unlikely outide of a lymph exposure. Injecting an HIV load into a lymph node might do it.
Since macrophages are produced in the bone marrow, as are T cells (though T's mature in the Thymus, hence the name), gene therapy directly to the uterine/vaginal/urethral area as suggested in the article would almost certainly be totally ineffective, since the macrophages patrolling the periphery will NOT dynamically uptake a defective gene and delete the properly functional endogenous copy.
Therefore, any gene therapy approach would have to target the pluripotent stem cells in the bone marrow of the individual. Needless to say, replacing these cells would not be an easy, cheap, or particularly safe operation to perform in the immediate future. While it is possible to irradiate an organism sufficiently to kill off the pluripotent stem cells in the marrow and then replace these cells (thus reconstituting the immune system before the organism dies of infection), this would not be a particularly feasible procedure.
More reasonably, a CCR5 binding humanized antibody might be effective (see the drug Antigren from Elan as a treatment for Crohns/MS) as something of a deterrent. The Immune system can react to antibodies after a time, however.
You are precisely right in mentioning the chemokine coreceptors.
CCR5 is the coreceptor (in fact, it has been _inconclusively_ demonstrated that CD4 may NOT be totally necessary to mediate viral entry of some strains into the cell, but the chemokine "co"receptors, that is CXCR4 or CCR5, absolutely are) which is present on the cell membrane of Macrophages, among other cell types. Macrophages are almost universally the first cell type infected in an HIV patient, regardles of whether the exposure route was sexual or by blood-blood contact.
This "immunity" against HIV infection so far as I know involves a truncated CCR5 gene, but NOT necessarily a truncated CXCR4 gene (as was previously assumed). The consequences of this are that the individual is simply NOT Immune to HIV infection in any normal sense of the word, but is for all intents and purposes incapable of *contracting* HIV in the first place through the normal routes unless Th (helper-T cells, typically CD4+) cells are directly exposed to HIV virus, something that would probably happen only if HIV were directly injected into the lymph.
Since Th cells do not possess CCR5, but rather CXCR4 which is not affected by the CCR5 mutation, T-tropic HIV strains could theoretically infect any individual with a mutated or nonexistant CCR5 gene assuming CXCR4 is not affected, which it is usually not. If the virus could get to the T-cells that is. Since they do not patrol the periphery, let alone extravasate out of capillaries into tissue, this is unlikely outide of a lymph exposure. Injecting an HIV load into a lymph node might do it.
Since macrophages are produced in the bone marrow, as are T cells (though T's mature in the Thymus, hence the name), gene therapy directly to the uterine/vaginal/urethral area as suggested in the article would almost certainly be totally ineffective, since the macrophages patrolling the periphery will NOT dynamically uptake a defective gene and delete the properly functional endogenous copy.
Therefore, any gene therapy approach would have to target the pluripotent stem cells in the bone marrow of the individual. Needless to say, replacing these cells would not be an easy, cheap, or particularly safe operation to perform in the immediate future. While it is possible to irradiate an organism sufficiently to kill off the pluripotent stem cells in the marrow and then replace these cells (thus reconstituting the immune system before the organism dies of infection), this would not be a particularly feasible procedure.
More reasonably, a CCR5 binding humanized antibody might be effective (see the drug Antigren from Elan as a treatment for Crohns/MS) as something of a deterrent. The Immune system can react to antibodies after a time, however.
