As with systemic immunity, the clinical consequences of HIV infection become apparent only with severe immune depletion. Intestinal disease caused by protozoa, mycobacteria, or cytomegalovirus is typically seen in patients with peripheral blood CD4 lymphocyte counts less than 100 cell/mm3. The widespread application of highly active antiretroviral therapy (HAART) has been associated with substantial mucosal immune reconstitution and a marked decrease in the incidence of enteric infections  (see below).
Several studies examined residual mucosal immune function in HIV infection. Scamurra and colleagues  studied the repertoire of immunoglobulin-producing cells in the lamina propria of HIV-infected and control subjects by immunohistochemistry. The density of Ig-producing cells was similar in both groups. Whereas the proportions of IgA-producing cells were lower in both the duodenum and colon from HIV-1-infected patients compared with controls, the density of IgG-producing cells was higher in the colon. These changes paralleled the results of studies of immunoglobulin concentrations in luminal contents. The investigators also evaluated the plasma cell repertoire and noted that it was relatively intact, suggesting that regulatory mechanisms provide sufficient diversity and effective induction and differentiation of mucosal B cells. Schafer and colleagues  studied secretory immunity during the course of SIV infection looking at tissue, serum and saliva. They corroborated the decrease in IgA and the increase in IgG. They were unable to detect SIV-specific IgA, although there was SIV-specific IgG. Incidentally, they also detected enteritis, indirectly, by showing increased albumen concentrations in luminal contents, indicating a breakdown in mucosal barrier function.
Cytotoxic T lymphocytes (CTL) may be important in anti-HIV host defense. Shacklett and colleagues  isolated HIV-specific CTL from duodenal and rectal biopsy specimens of chronically infected subjects. They were CD8 and MHC class 1 restricted in their function. Schmitz and colleagues , using a chronically infected SIV model, showed that the density of SIV gag-specific CD8 CTL in gastrointestinal mucosa is comparable to that seen systemically in SIVmac-infected rhesus monkeys.
HIV-1-specific mucosal IgA antibodies have been reported to correlate with protection in highly exposed but uninfected individuals, but are variably detected. Wright and colleagues  examimed rectal washes from HIV-1-infected and control subjects in a methodological validation study. Total IgA levels did not differ between HIV-1-infected and uninfected groups. HIV-1-specific IgA antibodies were absent in most samples, whereas HIV-1-specific IgG was found in most rectal washes of HIV-1-infected individuals. Schneider and colleagues  also found low levels of HIV-specific IgA antibody production after the short-term culture of duodenal biopsies in vitro.
These data suggest that cell-mediated immunity may be more important than secretory immunity in adaptive immunity to HIV. It should not be surprising that secretory immune function is irrelevant in the face of a chronic infection of the lamina propria. However, antibody-dependent cytotoxicity could be an important element of host defense in the intestine.
Relatively few reports of the effects of antiviral treatment in the gastrointestinal tract have been published. We compared the influence of antiretroviral therapy on intestinal mucosa and peripheral blood by performing studies immediately before, and 7 days after starting combination therapy . Many of the patients were antiretroviral naive, most had non-specific gastrointestinal symptoms, and none had detectable enteric infections. Treatment was associated with marked decreases in gastrointestinal symptoms. Similar relative declines in HIV-RNA contents and increases in CD4 lymphocyte counts were found in blood and mucosa (Fig. 8). Treatment was also associated with a fall in the number of apoptotic cells as measured by in-situ labeling, a change that correlated statistically with the change in mucosal viral burden. Talal and colleagues  evaluated the effects of 6 months of HAART in mucosal and peripheral blood mononuclear cells, and found that levels of multiply spliced HIV-1 RNA declined in parallel fashion in peripheral blood and mucosa, implying a decrease in replicating virus in both compartrments. Lampinen and colleagues  examined the effect of antiviral therapy on the detection of HIV RNA and DNA from rectal swabs in men who have sex with men. In that cross-sectional study comparing antiretroviral-treated to non-treated patients, therapy was associated with the suppression of RNA, but not DNA, suggesting latent viral infection in cell reservoirs.
Immune reconstitution in intestinal mucosa after the initiation of HAART can effectively restore mucosal immunity with clinical benefits, including the eradication of opportunistic pathogens such as cryptosporidia and microsporidia . Although the extent of immune reconstitution is substantial, it may, however, be incomplete. For example, Krzysiek and colleagues  studied the expression of CCR5 and the intestinal homing receptor integrin α4β7 on subpopulations of lymphocytes, and found a profound decrease of circulating α4β7+ lymphocytes and CCR5+ memory lymphocytes with non-lymphoid homing potential (CD62L−CD45RO+). This subpopulation remained depleted despite the control of viral replication with antiretroviral treatment. As protective immunity in vivo depends on lymphocytes carrying homing capacity to non-lymphoid tissue, the data suggest that immune dysfunction may persist despite effective antiviral therapy.
In summary, intestinal mucosa has long been known as a target for HIV and related viruses. Viral penetration through the epithelium appears to be receptor mediated and limited to CCR5 binding viruses. Viruses that bind CXCR4 may enter the intestinal compartment via the bloodstream. In either event, intestinal lymphocytes appear to be the initial target for HIV. There is compartmentalization of HIV infection, and different sequelae occur based on both viral and host factors. There is often an early and disproportionate loss of CD4 lymphocytes from the mucosal compartment, compared with peripheral blood. The mode of cell death appears to be apoptosis, and may include both infected and non-infected cells. Antiviral immunity includes both humoral and cell-mediated immune function, with the latter appearing more effective. Studies of antiviral therapy have shown that mucosal HIV is as sensitive to suppression as is plasma HIV, and there is a great capacity for immune reconstitution in intestinal mucosa. Finally, HIV may play a direct role in producing intestinal disease. Alterations in mucosal ion fluxes, which are associated with diarrhea, may result either from proinflammatory cytokine release from HIV-infected mononuclear cells in the lamina propria, or from gp120 interactions with certain G proteins expressed on the basolateral membranes of intestinal epithelial cells, leading to cytoskeletal changes and the opening of tight junctions.
1 Amerongen HM, Weltzin R, Farnet CM, Michetti P, Haseltine WA, Neutra MR. Transepithelial transport of HIV-1 by intestinal M cells: a mechanism for transmission of AIDS. J Acquir Immune Defic Syndr 1991; 4:760–765.
2 Fotopoulos G, Harari A, Michetti P, Trono D, Pantaleo G, Kraehenbuhl JP. Transepithelial transport of HIV-1 by M cells is receptor-mediated. Proc Natl Acad Sci USA 2002; 99:9410–9414.
3 Van de Perre P. Mother-to-child transmission of HIV-1: the ‘all mucosal’ hypothesis as a predominant mechanism of transmission. AIDS 1999; 13:1133–1138.
4 Meng G, Wei X, Wu X, Sellers MT, Decker JM, Moldoveanu Z, et al
. Primary intestinal epithelial cells selectively transfer R5 HIV-1 to CCR5+ cells. Nat Med 2002; 8:150–156.
5 Bouhlal H, Chomont N, Haeffner-Cavaillon N, Kazatchkine MD, Belec L, Hocini H. Opsonization of HIV-1 by semen complement enhances infection of human epithelial cells. J Immunol 2002; 169:3301–3306.
6 Hocini H, Bomsel M. Infectious human immunodeficiency virus can rapidly penetrate a tight human epithelial barrier by transcytosis in a process impaired by mucosal immunoglobulins. J Infect Dis 1999; 179(Suppl. 3):S448–S453.
7 Devito C, Broliden K, Kaul R, Svensson L, Johansen K, Kiama P, et al
. Mucosal and plasma IgA from HIV-1-exposed uninfected individuals inhibit HIV-1 transcytosis across human epithelial cells. J Immunol 2000; 165:5170–5176.
8 Neildez O, Le Grand R, Caufour P, Vaslin B, Cheret A, Matheux F, et al
. Selective quasispecies transmission after systemic or mucosal exposure of macaques to simian immunodeficiency virus. Virology 1998; 243:12–20.
9 Couedel-Courteille A, Butor C, Juillard V, Guillet JG, Venet A. Dissemination of SIV after rectal infection preferentially involves paracolic germinal centers. Virology 1999; 260:277–294.
10 Harouse JM, Gettie A, Tan RC, Blanchard J, Cheng-Mayer C. Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs. Science 1999; 284:816–819.
11 Poles MA, Elliott J, Vingerhoets J, Michiels L, Scholliers A, Bloor S, et al
. Despite high concordance, distinct mutational and phenotypic drug resistance profiles in human immunodeficiency virus type 1 RNA are observed in gastrointestinal mucosal biopsy specimens and peripheral blood mononuclear cells compared with plasma. J Infect Dis 2001; 183:143–148.
12 Adachi A, Koenig S, Gendelman HE, Daugherty D, Gattoni-Celli S, Fauci AS, Martin MA. Productive, persistent infection of human colorectal cell lines with human immunodeficiency virus. J Virol 1987; 61:209–216.
13 Fantini J, Yahi N, Delezay O, Gonzalez-Scarano F. GalCer, CD26 and HIV infection of intestinal epithelial cells. AIDS 1994; 8:1347–1351.
14 Nelson JA, Wiley CA, Reynolds Kohler C, Reese ChE, Margarettan W, Levy JA. Human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms. Lancet 1988; 2:259–262.
15 Fox CH, Kotler DP, Tierney AR, Wilson CS, Fauci AS. Detection of HIV-1 RNA in intestinal lamina propria of patients with AIDS and gastrointestinal disease. J Infect Dis 1989; 159:467–471.
16 Kotler DP, Reka S, Borcich A, Cronin WJ. Detection, localization,and quantitation of HIV-associated antigens in intestinal biopsies from patients with HIV. Am J Pathol 1991; 139:823–830.
17 Smith PD, Meng G, Sellers MT, Rogers TS, Shaw GM. Biological parameters of HIV-1 infection in primary intestinal lymphocytes and macrophages. J Leukoc Biol 2000; 68:360–365.
18 Meng G, Sellers MT, Mosteller-Barnum M, Rogers TS, Shaw GM, Smith PD. Lamina propria lymphocytes, not macrophages, express CCR5 and CXCR4 and are the likely target cell for human immunodeficiency virus type 1 in the intestinal mucosa. J Infect Dis 2000; 182:785–791.
19 Lapenta C, Boirivant M, Marini M, Santini SM, Logozzi M, Viora M, et al
. Human intestinal lamina propria lymphocytes are naturally permissive to HIV-1 infection. Eur J Immunol 1999; 29:1202–1208.
20 Anton PA, Elliott J, Poles MA, McGowan IM, Matud J, Hultin LE, et al
. Enhanced levels of functional HIV-1 co-receptors on human mucosal T cells demonstrated using intestinal biopsy tissue. AIDS 2000; 14:1761–1765.
21 Poles MA, Elliott J, Taing P, Anton PA, Chen IS. A preponderance of CCR5(+) CXCR4(+) mononuclear cells enhances gastrointestinal mucosal susceptibility to human immunodeficiency virus type 1 infection. J Virol 2001; 75:8390–8399.
22 Schneider T, Jahn HU, Schmidt W, Riecken EO, Zeitz M, Ullrich R. Loss of CD4 T lymphocytes in patients infected with human immunodeficiency virus type 1 is more pronounced in the duodenal mucosa than in the peripheral blood. Berlin Diarrhea/Wasting Syndrome Study Group. Gut 1995; 37:524–529.
23 Clayton F, Snow G, Reka S, Kotler DP. Selective depletion of rectal lamina propria rather than lymphoid aggregate CD4 lymphocytes in HIV infection. Clin Exp Immunol 1997; 107:288–292.
24 Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, et al
. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 1998; 280:427–431.
25 Kewenig S, Schneider T, Hohloch K, Lampe-Dreyer K, Ullrich R, Stolte N, et al
. Rapid mucosal CD4(+) T-cell depletion and enteropathy in simian immunodeficiency virus-infected rhesus macaques. Gastroenterology 1999; 116:1115–1123.
26 Fackler OT, Schafer M, Schmidt W, Zippel T, Heise W, Schneider T, et al
. HIV-1 p24 but not proviral load is increased in the intestinal mucosa compared with the peripheral blood in HIV-infected patients. AIDS 1998; 12:139–146.
27 Schmidt W, Fackler OT, Schafer M, Zippel T, Heise W, Mueller-Lantzsch N, et al
. Similar proviral load but increased HIV-1 p24 in the intestinal mucosa compared to the peripheral blood in HIV-infected patients. Ann NY Acad Sci 1998; 859:276–279.
28 Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, et al
. Apoptosis occurs predominantly in bystander cells and not productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med 1995; 1:129–134.
29 Boirivant M, Viora M, Giordani L, Luzzati AL, Pronio AM, Montesani C, et al
. HIV-1 gp120 accelerates Fas-mediated activation-induced human lamina propria T cell apoptosis. J Clin Immunol 1998; 18:39–47.
30 Mattapallil JJ, Reay E, Dandekar S. An early expansion of CD8alphabeta T cells, but depletion of resident CD8alphaalpha T cells, occurs in the intestinal epithelium during primary simian immunodeficiency virus infection. AIDS 2000; 14:637–646.
31 Ndolo T, Rheinhardt J, Zaragoza M, Smit-McBride Z, Dandekar S. Alterations in RANTES gene expression and T-cell prevalence in intestinal mucosa during pathogenic or nonpathogenic simian immunodeficiency virus infection. Virology 1999; 259:110–118.
32 Talal AH, Irwin CE, Dieterich DT, Yee H, Zhang L. Effect of HIV-1 infection on lymphocyte proliferation in gut-associated lymphoid tissue. J Acquir Immune Defic Syndr 2001; 26:208–217.
33 Clayton F, Cronin WJ, Reka S, Torlakovic E, Sigal S, Kotler DP. Rectal mucosal histopathology in HIV infection varies with disease stage and HIV protein content. Gastroenterology 1992; 103:919–933.
34 Kotler DP, Reka S, Clayton FC. Intestinal mucosal inflammation associated with human immunodeficiency virus infection. Dig Dis Sci 1993; 38:1119–1127.
35 Olsson J, Poles M, Spetz AL, Elliott J, Hultin L, Giorgi J, et al
. Human immunodeficiency virus type 1 infection is associated with significant mucosal inflammation characterized by increased expression of CCR5, CXCR4, and beta-chemokines. J Infect Dis 2000; 182:1625–1635.
36 Kotler DP, Gaetz HP, Klein EB, Lange M, Holt PR. Enteropathy associated with the acquired immunodeficiency syndrome. Ann Intern Med 1984; 101:421–428.
37 Kotler DP, Shimada T, Snow G, Winson G, Chen W, Zhao M, et al
. Effect of combination antiretroviral therapy upon rectal mucosal HIV RNA burden and mononuclear cell apoptosis. AIDS 1998; 12:597–604.
38 Stockmann M, Fromm M, Schmitz H, Schmidt W, Riecken EO, Schulzke JD. Duodenal biopsies of HIV-infected patients with diarrhoea exhibit epithelial barrier defects but no active secretion. AIDS 1998; 12:43–51.
39 Schmitz H, Rokos K, Florian P, Gitter AH, Fromm M, Scholz P, et al
. Supernatants of HIV-infected immune cells affect the barrier function of human HT-29/B6 intestinal epithelial cells. AIDS 2002; 16:983–991.
40 Bode H, Schmidt W, Schulzke JD, Fromm M, Zippel T, Wahnschaffe U, et al
. The HIV protease inhibitors saquinavir, ritonavir, and nelfinavir but not indinavir impair the epithelial barrier in the human intestinal cell line HT-29/B6. AIDS 1999; 13:2595–2597.
41 Clayton F, Kapetanovic S, Kotler DP. Enteric microtubule depolymerization in HIV infection: a possible cause of HIV-associated enteropathy. AIDS 2001; 15:123–124.
42 Dayanithi G, Yahi N, Baghdiguian S, Fantini J. Intracellular calcium release induced by human immunodeficiency virus type 1 (HIV-1) surface envelope glycoprotein in human intestinal epithelial cells: a putative mechanism for HIV-1 enteropathy. Cell Calcium 1995; 18:9–18.
43 Maresca P, Mahfoud R, Garmy N, Kotler DP, Fantini J, Clayton F. The virotoxin model of HIV-1 enteropathy: inhibition of gp120-induced experimental enteropathy by a synthetic soluble analog of galactosylceramide (GalCer), anti-GalCer and anti-GPR15/Bob antibodies. J Biomed Sci 2003; 10:156–166.
44 Clayton F, Kotler DP, Kuwada SK, Morgan T, Stepan C, Kuang J, et al
. Gp120-induced Bob/GPR15 activation: a possible cause of human immunodeficiency virus enteropathy. Am J Pathol 2001; 159:1933–1939.
45 Kotler DP, Orenstein JM. Prevalence of intestinal microsporidiosis in HIV-infected individuals for gastroenterological evaluation. Am J Gastroenterol 1994; 89:1998–2002.
46 Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al
. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853–860.
47 Scamurra RW, Nelson DB, Lin XM, Miller DJ, Silverman GJ, Kappel T, et al
. Mucosal plasma cell repertoire during HIV-1 infection. J Immunol 2002; 169:4008–4016.
48 Schafer F, Kewenig S, Stolte N, Stahl-Hennig C, Stallmach A, Kaup FJ, et al
. Lack of simian immunodeficiency virus (SIV) specific IgA response in the intestine of SIV infected rhesus macaques. Gut 2002; 50:608–614.
49 Carol M, Lambrechts A, Urbain D, van Vooren JP, Clumeck N, Goldman M, et al
. Persistent T cell and B cell activities in the duodenal mucosa of AIDS patients. AIDS 1998; 12:1763–1769.
50 Smit-McBride Z, Mattapallil JJ, McChesney M, Ferrick D, Dandekar S. Gastrointestinal T lymphocytes retain high potential for cytokine responses but have severe CD4(+) T-cell depletion at all stages of simian immunodeficiency virus infection compared to peripheral lymphocytes. J Virol 1998; 72:6646–6656.
51 Shacklett BL, Beadle TJ, Pacheco PA, Grendell JH, Haslett PA, King AS, et al
. Characterization of HIV-1-specific cytotoxic T lymphocytes expressing the mucosal lymphocyte integrin CD103 in rectal and duodenal lymphoid tissue of HIV-1-infected subjects. Virology 2000; 270:317–327.
52 Schmitz JE, Veazey RS, Kuroda MJ, Levy DB, Seth A, Mansfield KG. Simian immunodeficiency virus (SIV)-specific cytotoxic T lymphocytes in gastrointestinal tissues of chronically SIV-infected rhesus monkeys. Blood 2001; 98:3757–3761.
53 Belyakov IM, Ahlers JD, Brandwein BY, Earl P, Kelsall BL, Moss B, et al
. The importance of local mucosal HIV-specific CD8(+) cytotoxic T lymphocytes for resistance to mucosal viral transmission in mice and enhancement of resistance by local administration of IL-12. J Clin Invest 1998; 102:2072–2081.
54 Wilson LA, Murphey-Corb M, Martin LN, Harrison RM, Ratterree MS, Bohm RP. Identification of SIV env-specific CTL in the jejunal mucosa in vaginally exposed, seronegative rhesus macaques (Macaca mulatta
). J Med Primatol 2000; 29:173–181.
55 Ahmed RK, Nilsson C, Biberfeld G, Thorstensson R. Role of CD8+ cell-produced anti-viral factors in protective immunity in HIV-2-exposed but seronegative macaques resistant to intrarectal SIVsm challenge. Scand J Immunol 2001; 53:245–253.
56 Wright PF, Kozlowski PA, Rybczyk GK, Goepfert P, Staats HF, VanCott TC, et al
. Detection of mucosal antibodies in HIV type 1-infected individuals. AIDS Res Hum Retroviruses 2002; 18:1291–1300.
57 Schneider T, Zippel T, Schmidt W, Pauli G, Heise W, Wahnschaffe U, et al
. Abnormal predominance of IgG in HIV-specific antibodies produced by short-term cultured duodenal biopsy specimens from HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 16:333–339.
58 Talal AH, Monard S, Vesanen M, Zheng Z, Hurley A, Cao Y, et al
. Virologic and immunologic effect of antiretroviral therapy on HIV-1 in gut-associated lymphoid tissue. J Acquir Immune Defic Syndr 2001; 26:1–7.
59 Lampinen TM, Critchlow CW, Kuypers JM, Hurt CS, Nelson PJ, Hawes SE, et al
. Association of antiretroviral therapy with detection of HIV-1 RNA and DNA in the anorectal mucosa of homosexual men. AIDS 2000; 14:F69–F75.
60 Schmidt W, Wahnschaffe U, Schafer M, Zippel T, Arvand M, Meyerhans A, et al
. Rapid increase of mucosal CD4 T cells followed by clearance of intestinal cryptosporidiosis in an AIDS patient receiving highly active antiretroviral therapy. Gastroenterology 2001; 120:984–987.
61 Krzysiek R, Rudent A, Bouchet-Delbos L, Foussat A, Boutillon C, Portier A, et al
. Preferential and persistent depletion of CCR5+ T-helper lymphocytes with nonlymphoid homing potential despite early treatment of primary HIV infection. Blood 2001; 98:3169–3171.
62 Miao YM, Hayes PJ, Gotch FM, Barrett MC, Francis ND, Gazzard BG. Elevated mucosal addressin cell adhesion molecule-1 expression in acquired immunodeficiency syndrome is maintained during antiretroviral therapy by intestinal pathogens and coincides with increased duodenal CD4 T cell densities. J Infect Dis 2002; 185:1043–1050.