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Immune Activation/Inflammation and HIV Disease: an expanded summary of the IAS 2011 symposium

August 14, 2011

Immune activation during infection is usually a good thing, as it is necessary for clearance of the offending pathogen (1). During HIV infection, activation of innate immunity leads to decreased HIV replication via direct antiviral effects (1). However, in treated disease, where antiretroviral drugs directly control HIV replication, immune activation has more negative effects (1). Chronic immune activation during treated HIV infection leads to increased T cell turnover/exhaustion and lymph node fibrosis in HIV/AIDS patients (1). The life expectancy of HIV-infected individuals on HAART is 10 years shorter than your average person, and it is suspected that chronic immune activation is contributing to this (2).

Discovery of immune activation during HIV infection

Much of the pioneering work on immune activation during HIV infection was done by Janis Giorgi, who showed that HIV prematurely ages the immune system by driving the immune system into a “hyperactive frenzy” (3,4). She also discovered that CD38 expression, a marker of T cell activation, predicts survival time in HIV disease (3,5).

Causes of Immune Activation/Chronic Inflammation in HIV-infection

Although chronic immune activation in HIV infection was discovered relatively early in the HIV epidemic, it was a while longer before the causes were known. In 2006, when Brenchley et al published in Nature Medicine that microbial translocation was a cause of systemic immune activation during HIV infection (6), I was totally convinced.

Microbial translocation. Microbial translocation refers to the leaking of microbial products (LPS for example) out of the gut due to a breach in the mucosal barrier. This breach in


the mucosal barrier is thought to occur as a result of depletion of CD4+ cells in the gut during acute infection. When LPS or other microbial components enter the bloodstream as a result of this breach, they bind to TLR4, activating T cells, as shown in the illustration (from Chang & Altfeld) on the left. (7).

LPS has been measured in the plasma of HIV-infected individuals, and so this phenomenon is well-proven (6). However, due to results of a new study, it seems that the concept of microbial translocation is suddenly controversial.

In an attempt to reduce immune activation in HIV/AIDS patients, Anadis developed a product called BioGard – an oral therapy containing high affinity anti-LPS antibodies (1). If microbial translocation was causing chronic immune activation, then neutralizing LPS with antibodies should solve the problem. However, this is not what results of the study testing BioGard showed. Unfortunately, no effects on T cell activation or recovery were found in patients on this treatment (Bykawaga et al, J Infect Dis 2011, in press). Now some are concerned that microbial translocation may be an effect, and not necessarily a cause of chronic immune activation (1,3). However, it is important to note here that LPS is not the only microbial component that could be entering the bloodstream as a result of microbial translocation. It is possible that with LPS neutralization, other microbial components are still activating the immune system via TLR4.

This begs the question, “If microbial translocation is not causing immune activation, then what is?” As it turns out, there are several other potential causes of chronic immune activation during HIV infection. Steven Deeks gave an excellent overview at IAS of all the known causes of chronic immune activation during HIV infection. I will discuss each one briefly below:

Residual HIV replication. It seems that some of the immune activation during HIV replication should be due to virus itself, as HIV has been shown to activate T cells via TLR7 in vitro (7). Additionally, virus replication and immune activation levels correlate in the certain tissues (3). If low-level HIV replication is causing immune activation in vivo in patients on HAART, then intensification of antiretroviral therapy should result in decreased immune activation along with decreased viral replication. To test this, raltegravir intensification studies were performed to see if levels of immune activation would be changed as a result of reduced residual viral replication in HIV patients on intensified antiretroviral therapy including raltegravir. At the moment, two such studies were done, each with different results. The Hatano study showed no change in T cell activation (3,8). However, a larger, more definitive, study showed decreased immune activation in conjunction with decreased HIV replication in ~1/3 of HAART-suppressed subjects as a result of raltegravir intensification (3,9). When raltegravir treatment was terminated in these individuals, immune activation went back up (3,9). The results of these studies, when combined, suggest that residual HIV replication is not a major cause of immune activation in HIV patients on HAART. However, in a percentage of people, it does have a minor effect on the level of immune activation.

CMV (and other prevalent coinfections). There is plenty of good evidence to suggest that co-infecting pathogens can elicit “massive” immune responses in HIV-infected individuals. Coinfection with herpesviruses like CMV and EBV is common in HIV-infected individuals (2). In normal, healthy young adults, 1/10 T cells are CMV positive, and CMV-specific T cell responses are 3-5 fold higher in HIV-infected individuals (3,10,11). It has been estimated that 20-25% of residual immune activation in HIV infection is due to CMV-specific T cell responses (1). Using valganciclovir treatment for reduction of CMV replication, immune activation in HIV patients can be reduced (2).

Consequences of Immune Activation/Chronic Inflammation in HIV-infection

Things can get confusing once you try to tease out the causes vs. the consequences of immune activation/chronic inflammation. Originally considered to be a cause of immune activation, microbial translocation is now considered to possibly be a consequence. Deeks discussed damage to the lymph nodes during HIV infection as a cause of immune activation. However, most of the lymph node damage during HIV infection, according to Tim Schacker’s talk at CROI, is a consequence of inflammation.

Damage to the lymph nodes. For the “lymph node story”, I will be giving a summary of Tim Schacker’s CROI talk (online at http://app2.capitalreach.com/esp1204/servlet/tc?c=10164&cn=retro&s=20445&&dp=player.jsp&e=13721&mediaType=audio), as this was recommended by Deeks. HIV replicates, and takes its biggest toll, in lymphoid tissues (2). After HIV-induced damage to lymphoid tissues, lymphoid populations don’t fully come back, and few individuals reconstitute immunity to normal levels (2,12,13,14,15). A reason why immune reconstitution is impaired in HIV-infected individuals is tissue damage resulting from chronic inflammation, especially in the lymph nodes (2). In the lymph nodes, chronic inflammation disrupts the fibroblast reticular cell (FRC) network necessary for effective antigen presentation (see Fig 3 from J Clin Invest. 2011 March 1; 121(3): 998–1008 below) (2,16). During HIV infection, fibroblasts in the lymph nodes are stimulated to deposit collagen, which traps the T cells (2). Trapped by all the collagen, the T cells die due to lack of access to IL-7 and other nutrients (2,17).


Key: uninfected (A), infected (B), collagen (red), FRC network (green), CD3+ T cells (blue)

Metabolic complications. Outside of the context of HIV infection, inflammation is known to cause various metabolic disorders, including obesity and insulin resistance (18). Since there is evidence of metabolic disorders and chronic inflammation during HIV infection, there is likely a link between these two during HIV infection. Georg Behrens, president of the German AIDS Society, has long been interested in the role that inflammation plays in the development of metabolic complications during HIV disease. In his talk at IAS, he discussed the link between inflammation and metabolism outside HIV. Behrens gave three examples of how inflammation and metabolism are linked:

  1. Atherosclerosis as an inflammatory disease (19)
  2. Inflammatory infiltration of fat tissue in obesity. Inflammation may drive differentiation of anti-inflammatory M2 macrophages, present in the fat tissue of lean individuals with normal metabolic function, into M1 macrophages, more commonly found in the fat tissue of the obese. During inflammation, effector T cells can even recruit M1 macrophages into fat tissue, thereby increasing metabolic dysfunction (20).
  3. Suppression of insulin signaling by inflammatory mediators. insulin signaling is suppressed by inflammatory cytokines and mediators such as IL-6, TNF-alpha, and LPS, causing insulin resistance (21).

This brings us to the question: How are inflammation and metabolic disorders linked during HIV infection? Insulin resistance occurs in HIV-infected patients, although inflammation has not yet been proven as a cause in this context. At the moment, metabolic complications in HIV patients are blamed mostly on HAART (18). There is some evidence of increased cardiovascular disease in HIV patients, which is likely due to chronic inflammation (18).

Increased T cell turnover. Early studies by J. Giorgi and others showed rapid T cell turnover in HIV infection (1,4).

Interventions to reduce inflammation and immune activation in treated HIV infection

Now that more is known about the causes and the effects of chronic immune activation during HIV infection (see summary chart below from Peter Hunt’s talk), more attempts are being made to reduce inflammation and immune activation during HIV infection. These attempts were the subject of Peter Hunt’s IAS talk.




Thus far, attempts to control inflammation and immune activation in HIV infection have been mostly unsuccessful, and Peter’s talk focused on what we can learn from these unsuccessful attempts, described below. Peter cited the ESPRIT and SILCAAT IL-2 studies and maraviroc intensification studies as two unsuccessful attempts to control immune activation in HIV patients.

IL-2 is known to decrease immune activation as measured by T cell proliferation in HIV infection. Interestingly, it’s been found that T cells expand in IL-2-treated HIV patients, while T cell proliferation decreases (22). Unfortunately, IL-2 treatment had no clinical benefits although CD4 counts improved and IL-2 decreases T cell activation as measured by HLA-DR and CD38 expression (1,23). This study really makes you wonder how we should measure immune function and activation in HIV patients, as current measures did not accurately predict a better clinical outcome in this study.

Hunt gave his own Maraviroc intensification study as an example of a failed attempt to control immune activation during HIV infection. Maraviroc blocks CCR5, and Peter thought there was a chance this would bring down immune activation by blocking trafficking to sites of inflammation. However, this treatment actually increased immune activation in HIV patients.

Based on the results of these studies, Hunt feels that more targeted approaches are more likely to be successful. Now that the causes of immune activation during HIV infection are known, more successful treatments targeting specific causes of activation are being developed. For example, valganciclovir treatment for CMV replication reduced immune activation in HIV patients, as described above (2). Anti-LPS antibodies used to treat microbial translocation-induced immune activation were unsuccessful, but chloroquine treatment to block TLRs gave reduced T cell activation (1). Finally, raltegravir intensification to treat immune activation directly induced by HIV components was successful in a population of individuals, as previously mentioned. In conjunction with HAART, these types of immune therapies have the potential to further increase the life expectancy of HIV-infected individuals.

Citations:

(1) Hunt, P. 2011, “Interventions to Reduce Inflammation and Immune Activation in Treated HIV Infection”, 6th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, Rome, Italy, http://pag.ias2011.org/session.aspx?s=91

(2)Schacker, T. 2011, “Chronic Inflammation in HIV Disease”, CROI, Boston, Massachusetts, Hynes Convention Center, http://retroconference.org/2011/data/files/webcast_2011.htm

(3)Deeks, S.G. 2011, “The pathogenesis of persistent HIV-associated inflammation during long-term antiretroviral therapy”, 6th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, Rome, Italy, http://pag.ias2011.org/session.aspx?s=91

(4)Effros RB, Allsopp R, Chiu CP, Hausner MA, Hirji K, Wang L, Harley CB, Villeponteau B, West MD, & Giorgi JV (1996). Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS (London, England), 10 (8) PMID: 8828735

(5) Giorgi, J., Hultin, L., McKeating, J., Johnson, T., Owens, B., Jacobson, L., Shih, R., Lewis, J., Wiley, D., Phair, J., Wolinsky, S., & Detels, R. (1999). Shorter Survival in Advanced Human Immunodeficiency Virus Type 1 Infection Is More Closely Associated with T Lymphocyte Activation than with Plasma Virus Burden or Virus Chemokine Coreceptor Usage The Journal of Infectious Diseases, 179 (4), 859-870 DOI: 10.1086/314660

(6) Brenchley, J., Price, D., Schacker, T., Asher, T., Silvestri, G., Rao, S., Kazzaz, Z., Bornstein, E., Lambotte, O., Altmann, D., Blazar, B., Rodriguez, B., Teixeira-Johnson, L., Landay, A., Martin, J., Hecht, F., Picker, L., Lederman, M., Deeks, S., & Douek, D. (2006). Microbial translocation is a cause of systemic immune activation in chronic HIV infection Nature Medicine, 12 (12), 1365-1371 DOI: 10.1038/nm1511

(7) Chang, J., & Altfeld, M. (2008). TLR-mediated immune activation in HIV Blood, 113 (2), 269-270 DOI: 10.1182/blood-2008-10-184598

(8) Hatano H, Hayes TL, Dahl V, Sinclair E, Lee TH, Hoh R, Lampiris H, Hunt PW, Palmer S, McCune JM, Martin JN, Busch MP, Shacklett BL, & Deeks SG (2011). A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. The Journal of infectious diseases, 203 (7), 960-8 PMID: 21402547

(9) J Buzón, M., Massanella, M., Llibre, J., Esteve, A., Dahl, V., Puertas, M., Gatell, J., Domingo, P., Paredes, R., Sharkey, M., Palmer, S., Stevenson, M., Clotet, B., Blanco, J., & Martinez-Picado, J. (2010). HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects Nature Medicine, 16 (4), 460-465 DOI: 10.1038/nm.2111

(10) Sylwester, A. (2005). Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects Journal of Experimental Medicine, 202 (5), 673-685 DOI: 10.1084/jem.20050882

(11) Naeger DM, Martin JN, Sinclair E, Hunt PW, Bangsberg DR, Hecht F, Hsue P, McCune JM, & Deeks SG (2010). Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease. PloS one, 5 (1) PMID: 20126452

(12) Mehandru S, Poles MA, Tenner-Racz K, Jean-Pierre P, Manuelli V, Lopez P, Shet A, Low A, Mohri H, Boden D, Racz P, & Markowitz M (2006). Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS medicine, 3 (12) PMID: 17147468

(13) Schacker TW, Reilly C, Beilman GJ, Taylor J, Skarda D, Krason D, Larson M, & Haase AT (2005). Amount of lymphatic tissue fibrosis in HIV infection predicts magnitude of HAART-associated change in peripheral CD4 cell count. AIDS (London, England), 19 (18), 2169-71 PMID: 16284469

(14) Kelley CF, Kitchen CM, Hunt PW, Rodriguez B, Hecht FM, Kitahata M, Crane HM, Willig J, Mugavero M, Saag M, Martin JN, & Deeks SG (2009). Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 48 (6), 787-94 PMID: 19193107

(15) Gandhi RT, Spritzler J, Chan E, Asmuth DM, Rodriguez B, Merigan TC, Hirsch MS, Shafer RW, Robbins GK, Pollard RB, & ACTG 384 Team (2006). Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1-positive subjects: results from ACTG 384. Journal of acquired immune deficiency syndromes (1999), 42 (4), 426-34 PMID: 16810109

(16) Schacker, T., Brenchley, J., Beilman, G., Reilly, C., Pambuccian, S., Taylor, J., Skarda, D., Larson, M., Douek, D., & Haase, A. (2006). Lymphatic Tissue Fibrosis Is Associated with Reduced Numbers of Naive CD4+ T Cells in Human Immunodeficiency Virus Type 1 Infection Clinical and Vaccine Immunology, 13 (5), 556-560 DOI: 10.1128/CVI.13.5.556-560.2006

(17)Zeng M, Smith AJ, Wietgrefe SW, Southern PJ, Schacker TW, Reilly CS, Estes JD, Burton GF, Silvestri G, Lifson JD, Carlis JV, & Haase AT (2011). Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. The Journal of clinical investigation, 121 (3), 998-1008 PMID: 21393864

(18) Behrens, G. 2011, “Inflammation and metabolic complications in HIV disease”, 6th IAS Conference on HIV Pathogenesis, Treatment, and Prevention, Rome, Italy, http://pag.ias2011.org/session.aspx?s=91

(19) Hansson, G., & Libby, P. (2006). The immune response in atherosclerosis: a double-edged sword Nature Reviews Immunology, 6 (7), 508-519 DOI: 10.1038/nri1882

(20) Ouchi N, Parker JL, Lugus JJ, & Walsh K (2011). Adipokines in inflammation and metabolic disease. Nature reviews. Immunology, 11 (2), 85-97 PMID: 21252989

(21) Tilg, H., & Hotamisligil, G. (2006). Nonalcoholic Fatty Liver Disease: Cytokine-Adipokine Interplay and Regulation of Insulin Resistance Gastroenterology, 131 (3), 934-945 DOI: 10.1053/j.gastro.2006.05.054

(22) Sereti I, Anthony KB, Martinez-Wilson H, Lempicki R, Adelsberger J, Metcalf JA, Hallahan CW, Follmann D, Davey RT, Kovacs JA, & Lane HC (2004). IL-2-induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation. Blood, 104 (3), 775-80 PMID: 15090457

(23) Abrams D (2009). Interleukin-2 Therapy in Patients with HIV Infection New England Journal of Medicine, 361 (16), 1548-1559 DOI: 10.1056/NEJMoa0903175

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