In Figure 1, the stages of intestinal lymphoid tissue are shown to depict events that may follow in the wake of HIV infection. In (A), normal intestinal lymphoid tissue, naïve
Figure 1: Anatomical arrangement of the inductive site of normal immune responses in Peyer’s patches and lymphoid follicles in GALT and CD4+ T cell distribution in the lamina propria upon HIV infection (adapted from Veazey & Lackner49 and Cohen50.
Inductive site (Peyer’s patch, lympoid follicles)
Effector site (Intestinal villi, lamina propria)
B Acute HIV
infection
C Chronic HIV
infection
HIV-infected CD4+ cell Activated CCR5+CD4+ T cell
Naive CD4+ T cell A Normal intestinal
lymphoid tissue Mesenteric lymph node
Recirculation
CD4+ T-cells reside in the inductive sites of the lymphoid follicles. Immune responses are initiated in the follicles and mesenteric lymph nodes (MLNs), where T-cells are unavoidably exposed to small but significant quantities of a variety of antigens normally found in the intestinal tract, such as dietary and microbial antigens. The CD4+ T-cells become activated, co-express CCR5, and ultimately (see above) migrate to the effector sites in the lamina propria, where they reside in large numbers36. It has recently been shown that the Vitamin A metabolite, retinoic acid, can facilitate this cell migration to the effector sites and aid immunity in the intestine47, 48.In acute HIV infection (B), the activated CCR5+ CD4+ T-cells are targets for HIV infection and replication and die either through direct infection or powerful bystander effects that coincide with peak viraemia in the plasma and the emergent rise of CD8+ virus-specific in the circulation. The eventual rapid decline in plasma viraemia may not be principally caused by the effector CD8+ T-cells, as previously thought, but rather to the greatly diminished numbers of target CCR5+ CD4+ T-cells residually resident in the gut wall. As HIV infection progresses to the chronic stage, which is for a time characterized by persistent viral infection more-or- less counter-balanced by replacement of new T-cells migrating into the bowel wall, net loss of CCR5+ CD4+ T-cells (C) ensues when the rate of T-cell activation, in the face of the immune suppressive effects of T regs in the lamina propria against the background of a general “oral tolerance regime” of a normal bowel wall, provides enough targets for viral replication and associated apoptotic T-cell deaths to overcome the defences, so to speak, and usher in the slow or rapid decompensating phase of grossly immune-deficient AIDS, leading to death from repeated, progressively more serious opportunistic infections or cancers in various locations.
The widely held notion that robust T-cell immunity to HIV in the peripheral circulation, as outlined earlier in this chapter, may exert strong pressure on viral replication such as to maintain a steady-state of viral replication resulting in a set-point of viraemia, may now well turn out be a misplaced judgement. Indeed, recent data from Reynolds, et al51 have shown that the identified strong CD8+ virus-specific responses in monkeys after they were given SIV were minimal or not found in GALT, but rather occurred mostly in the cervico-vaginal tissues. The conclusions made were that specific strong CD8+ T-cell immunity initiated by the host cannot prevent the huge CD4+ T-cell depletion occurring in gut tissue, and the responses identified in the peripheral circulation are too late and too little to obviate viral persistence in this location, and disease progression as described above. Steady-state T cell activation within the effector sites of the GALT, due to continued gut-derived antigen encounter, may be the single most important factor which maintains a pool of CD4+ T-cell targets for HIV infection and replication, supporting viral persistence and the eventual failure of viral control by the body.
Microbial translocation in the gut during chronic HIV infection has now been shown to be one of the major driving forces behind immune activation and maintaining the pool of activated CD4+ T-cells that can be productively infected by the virus52. The levels of plasma lipolysaccharide (LPS, an endotoxin to the human body derived from Gram-negative bacteria resident as part of the gut flora), in HIV-infected individuals during the chronic stage of disease and during AIDS have been found to be much higher than in healthy HIV-negative controls or in subjects newly infected with HIV. Plasma LPS appeared to be derived from bacteria crossing into the blood circulation from the intestine and colon during HIV infection, probably as a result of mucosal malfunction induced by the virus, directly or indirectly. Similar types of bacterial translocation have also been observed in patients receiving radiation therapy and in those that suffer from inflammatory bowel disease. Concomitant with increased plasma LPS was increased plasma soluble CD14, a receptor molecule found on the surfaces of monocytes and shed upon in vivo activation by LPS. Interestingly, HIV-infected individuals who were able to control viral replication and appeared clinically healthy had higher levels of endotoxin- core antibodies that seemed to neutralize the chronic inflammation-activating effects of LPS in the systemic circulation. Along with data to show that provision of antiretroviral drug treatment resulted in lowered plasma LPS levels as well as lowered T-cell activation, the study has provided evidence that it may be the continuing presence of HIV in GALT that causes regular microbial translocation resulting in a degree of immune activation that maintains viral replication in susceptible cells and ultimately drives the slow collapse of the immune system, as described above. The plasma levels of an acute- phase (inflammatory) protein , C-reactive Protein (CRP), has recently been positively associated with progression time to AIDS in HIV-infected subjects53. The crucial link that needs to be made is whether different nutrients/dietary components affect gut mucosal integrity in HIV-infected individuals in systematic or individually different ways, which could influence or determine the course of HIV pathogenesis through effects on the basic processes of viral persistence and net CD4+ T-cell depletion, by influencing the rate of microbial translocation.
The notion that chronic HIV infection may manifest as a form of inflammatory bowel disease urgently requires the bringing together of two, possibly three major fields on enquiry in the health sciences in HIV medicine/biology, clinical/scientific gastroenterology (specifically where it relates to chronic inflammatory disorders), and nutrition (specifically where this relates to the burgeoning field of probiotics and prebiotics (see Chapter 4).
Much is now known, for example, about the underlying molecular and genetic basis of Crohn’s Disease54, and therapy involving drugs such as 5-aminosalicylic acid55 and elemental or polymeric diets (in children) is well-characterised56.It may be relevant that
5-aminosalicylates, which have become a standard, effective therapy for inflammatory bowel disease, have also successfully been used in the context of HIV-related enteropathy57. Beneficial effects of probiotics and/or prebiotics in numerous clinical situations58-60 may well be replicable in chronic HIV infection.
It is possible that the topic of diet and nutrition in relation to the HIV pandemic may acquire a new and exciting dimension that goes beyond traditional pre-occupations with nutrient deficiencies actively to explore therapeutic approaches aimed at the optimum functioning of the intestines in infected subjects, generated in a productive, interdisciplinary environment.
of infancy and of infancy and
childhood
childhood
Nutrition, HIV infection and
active TB in infants and children
HIV and TB are infectious diseases that contribute significantly to infant and child morbidity and mortality in developing-country settings. The pathogenesis of HIV infection may depend on both virological factors (viral strain and phenotype) and host factors (genetic and nutritional).
Nutritional deficiencies may play a role in the pathogenesis of HIV infection partly because of the role of some micronutrients as anti-oxidants and/or in immune function (see Chapter 7).