Gut memory CD4 T cells implicated in a central role for HIV disease pathology: dramatic impact prior to seroconversion
Gareth Hardy, HIV i-Base
Daniel Douek of The Vaccine Research Centre, NIAID, NIH, Bethesda, MD, USA proposed a model of HIV pathogenesis in which the loss of CD4 T cells is a result of an early massive infection and deletion of memory CD4 T cells, followed by exhaustion of the CD4 T cell pool as a result of chronic immune activation.
Douek showed that during the first 17 days of SIV infection in rhesus macaques the loss of CD4 T cells in the blood was relatively minor, as it was in mesenteric and inguinal lymph nodes. However, in the jejunum of the gut, mucosal T cells were reduced by 80% during this short period. Because most memory T cells reside in the gut, rather than the blood or lymph nodes and both HIV and SIV infect memory cells with a CCR5+ phenotype, Douek looked more specifically at changes in memory T cells. Interestingly, memory T cells were reduced by 80% in the blood, lymph nodes and the mucosa of the gut within the first 17 days of SIV infection.
Douek then presented data from a patient who had very early HIV infection (before seroconversion), compared to an uninfected control, showing a very large expansion of CCR5+ CD8 T cells in the blood and lymph nodes. This is consistent with other viral infections such as EBV and CMV. This expansion does not occur for CD4 T cells. The percentage of cells expressing CCR5 is shown below in table 1.
Table 1: Percentage of cells expressing CCR5
|HIV –||HIV +||HIV –||HIV +|
However, a complete loss of CCR5+ CD4 memory T cells was observed in the gut of this patient*. Further more Douek showed photographic images taken by colonoscopy from these two individuals, revealing a marked reduction in the lymphoid tissue of the terminal illium in this patient. Biopsies of the mucosa revealed total loss of CD4 T cells from their Peyer’s patches. Going back to the macaque/SIV model Douek and colleagues quantified the infected fraction of memory CD4 T cells in each of these compartments by single cell qPCR for SIV gag. In the blood 30% of CD4 T cells were found to be infected, in the lymph nodes around 50% were infected and 60% were infected in the gut mucosa. Therefore the rate of infection of memory CD4 T cells in acute infection is more than 100-fold higher than in chronic infection.
Douek’s new hypothesis of HIV pathology proposes that the majority of memory CD4 T cells are lost during acute infection, and that the loss of these cells can be solely ascribed to the consequences of viral infection. Taking this as the initial insult to the CD4 T cell pool, the ensuing immune activation that characterises chronic infection leads to a persistent drive of CD4 T cells through successive rounds of activation and death, gradually draining the memory CD4 T cell compartment in an effort to maintain homeostasis.
Douek points to the example of chemotherapy in bone marrow transplantation, in which CD4 T cell reconstitution is limited and dependant both on age and intact lymph node architecture, unlike CD8 T cell reconstitution, which is mainly driven by peripheral expansion. In response to the direct infection-associated and activation-associated depletion in CD4 T cell numbers, the body tries to reconstitute them by producing more. However in HIV/SIV infection the local lymph node microenvironments and thymic out-put are significantly damaged.
With the accumulation of “effector-type” T cells in the lymph nodes they begin to resemble sites of peripheral inflammation, rather than sites of normal T cell homeostasis. The lymph node architecture is destroyed, as these sites become fibrosed, where normal tissue is replaced by collagen. Douek’s own data here shows a strong correlation between the percentage of “effector-type” CD4 or CD8 T cells in the lymph node and the percentage of collagen per mm2 of tissue (p values not shown). Futhermore, Douek positively correlates the percentage of collagen deposition per mm2 of lymph node tissue with a poor CD4 T cell count increase following initiation of anti-retroviral therapy, regardless of baseline CD4 T cell count.
Therefore, Douek hypothesises that CD4 T cell reconstitution is vulnerable because of the suppression of thymic out-put and destruction of local lymph node architecture, whereas the CD8 T cell reconstitution is not as it more independent of these sites. Douek claims that this explains why CD4 T cell numbers diminish as a result of viral infection and deletion during acute infection in the first instance and in the second instance by the homeostatic strain placed on them by immune activation during chronic infection.
This presentation points in the direction of an interesting story involving lymphoid tissue in the gut. However, the observational data involving endoscopy, biopsy and CCR5 are based on a single patient, and although the SIV model supports this theory, there was little statistical analysis included in the presentation and no p-values shown relating to collagen in lymph tissue and CD4 count. Longitudinal data on this individual patient would help.
Although research in primary infection involving endoscopy is hard to reproduce due to practical and ethical concerns, it was not clear whether these early changes were expected to reverse during chronic infection.
Douek D. Making Sense of HIV Disease Pathogenesis. 12th CROI 2005.
Oral abstract 127.