So these are all normal results: what was atypical about C135? It turns out that apart from the bad luck of receiving a transfusion containing HIV in the first place, he has otherwise had the good luck to benefit from five separate factors that suppress HIV replication and encourage a strong and specific immune response against it.
Subject C135 appears to have a unique combination of fortunate circumstances that only serve to show how difficult it is to eliminate HIV infection once it is established.
The first is the defining characteristic of the SBBC patients: the virus shared between donor and recipients has a piece of DNA missing that encodes a viral gene called nef (negative regulatory factor). Nef amplifies T-cell activation, thus providing new cells for the virus to infect, degrades a cellular antiviral defence called CTLA-4, and sends out a false activation signal from cells that keeps the immune system on alert. The virus was also lacking a section called LTR (long terminal repeat) that acts like the cap at the end of a shoelace, preventing the viral DNA from “fraying”.
Although nef-deficient virus replicates slowly and people with it tend to have lower viral loads, it is not disabled and will eventually cause immune damage to most people.
However the patient had several other characteristics that slowed viral replication still further. The second characteristic is that he was what is called heterozygous for the CCR5 gene. This means that, like 8-10% of people of north European ancestry, he had only one copy of the gene that peppers the surfaces of CD4 cells with the co-receptor molecule CCR5. People with no CCR5 genes – about 1% of north Europeans – are virtually immune to HIV. C135 had 48% of the normal complement of CCR5. It was still possible to infect cells cultured from him in the lab dish with new strains of HIV, but his HIV-suppressant CD8 cells had to be killed before infection could take place.
The third characteristic is that although his immune system was in general not overly responsive to HIV, his CD4 cells had a very potent and specific response to a 15-amino-acid length of the HIV gag (shell) protein. These peptides, or short sections of protein, are what virally-infected cells display on their surfaces in order to “call for help” and signal that they are infected. When these stimulate an immune response, they are called epitopes. In other words, C135’s CD4 cells were unusually alert to a particular and very specific signal of viral infection. In response they quickly issued the cell-signalling chemical Interleukin-2 (IL-2) to direct CD8 cells to destroy them.
C135’s fourth characteristic is that he had two cellular immune genes that ensured his response to HIV was particularly efficient, HLA-B57 and HLA-DR13. HLAs (human leukocyte antigens) are the cell-surface molecules that “present” epitopes to the immune system, and some may do this more efficiently than others.
HLA-B57, in particular, is known for two things. Firstly, people with the B5701 variety of this are allergic to the antiretroviral drug abacavir and cannot take it. Secondly, however, HLA-B57 – and HLA-DR13 – are associated with lower HIV viral loads and slower progression. Fifty per cent of long-term non-progressors who stay well off ART for many years have HLA-B57, even though only 1.5% to 5% of most populations carry it.
Subject C135’s sharp CD4 response to HIV was not caused by his having HLA-B57. Rather, the HLA type acted as an intermediary. Once his CD4 cell had fired off IL-2 as an instruction to destroy HIV-infected cells, the efficiency with which his HLA-57 displayed HIV in the surface of cells meant that the effect of the IL-2 was amplified and speeded up, ensuring his fifth and final characteristic, and the one that has probably purged all the HIV-infected cells from his body: a strong and broad CD8 (T-suppressor) cell response to HIV-infected cells. This response was weak unless the CD8 cells were cultured alongside the CD4 cells, showing that the CD4 HIV response needed to happen first, before the CD8 cells ‘understood’ that they had to kill HIV-infected cells.
So C135’s response to HIV was so potent partly it is probably because his virus was slow to replicate and so, during initial infection, his
immune system had a chance to develop an effective and specific anti-HIV response,
before HIV had a chance to mutate away from vulnerability to that
response - what’s been called “immune escape”. HIV usually wins the
“arms race” between the body’s immune response and its ability to avoid it, but may occasionally lose the race in situations like this, or during
very early treatment, or if already primed to recognise HIV with a
In addition, however, he had genetic factors that ensured this early immune response was particularly fast and efficient, which may have ensured that his already slow-acting HIV never had the time to develop resistance to the immune response. Instead, that response did what it does with the majority of viruses that are not HIV - it cleared it.