Understanding mechanisms for host defense in HIV-1 infection is probably necessary for planning a treatment or development of a drug or vaccine or gene therapy for HIV1 infection

Authors

o    *Professor Pranab Kumar Bhattacharya MD(cal), FIC Path(Ind),  Professor and Head, Dept. of Pathology; *Miss Upasana Bhattacharya –  Only daughter of Prof. P.K. Bhattacharya ;

o    **Rupak Bhattacharya BSc(cal),MSc(JU);**Ritwik Bhattacharya B.com(cal); **Soumyak Bhattacharya BHA;** Rupsa Bhattacharya of residence 7/51 Purbapalli, Sodepur, Kol-110;  ***Dalia Mukherjee BA(hons) cal, ***Miss Oindrila Mukherjee*** Mr Debasis  Mukherjee BSc(cal)  of residence Swamijinagar,  South Habra 24 parganas(north) W,B India

o     *Calcutta School of Tropical Medicine, 108 C.R avenue, Calcutta-73, W,B ,India* *  of residence 7/51 Purbapalli,  PO Sodepur, Dist 24 parganas(north) West Bengal  Kol-110 *** residence Swamijinagar,  South Habra 24 parganas(north) W,B India

The medical community became aware of AIDS, 34 years ago. Since then, global HIV and AIDS pandemic caused approximately 60 million infections. Experts estimated that more than 25 million people already died of AIDS, and > 33 million currently are living with HIV infection or AIDS.  The HIV epidemic in India, described as series of epidemics, heterogeneous in nature, varying with respect to prevalence levels, risk factors for infection and its transmission pattern. Some epidemic appeared  stable or diminishing in some parts of the south India, while others are growing at a modest rate elsewhere especially in  north east regions in spite of ART .

 There's a mantra, in AIDS field: HIV infection can be managed and treated with antiretroviral drugs. But ART could not cure AIDS could never. At the 32-years mark in HIV epidemic, it is critical to acknowledge that there are no documented cases of a true cure induced by ART, though ART is very effective in suppressing detectable viral replication for extended periods. Problems of ART remained in many of their toxicity, complications, drug resistance and failure of adherence to drug due to cost.  Final solution for AIDS treatment is not   probably a potential or combination anti retroviral drugs or a preventive vaccine, or   Microbiocide (gels or vaginal ring) prPrEp(protection  is 39%-54%) or pre expose prophylaxis initiative (success rate-44%) or male circumcision(success rate 50-60%)  or VOICE trial , rather but a therapeutic vaccine, aimed at complementing the antiretroviral therapy given to many patients, so that their immune systems can defend themselves. “Nature showed us a few percent of people in which though they are infected by HIV1, but they are not sick by the virus for long 20 years or more. So the idea is to make such a vaccine for most of these people, infected people, who never sick, for life.”

Understanding mechanisms for host defense in HIV-1 infection

During acute HIV infection in adults, a peak of ~10⁷ HIV RNAs/ml plasma is followed by a  marked decline, over  few weeks, to around 30,000 RNAs/ml concomitantly with  appearance of HIV-specific CD8+cytotoxic T lymphocyte (CTL) responses, suggesting  CTLs  responsible for reducing virus levels[1,3]. Furthermore, blocking these cells, by administering CD8-specific monoclonal antibodies prohibits immune mediated reduction in viral load. Persistent control of HIV-1 infection is associated with  presence of CD8+ T cells , capable of producing not only IFN gamma  following contact with the cognate peptide –MHC complex, but also other cytokines, such as IL-2 and chemokines, including RANTES and MIP- 1a, which are capable of blocking viral entry through occupancy of  HIV co-receptor CCR5. HIV-specific CD8+ T cells release granzyme and perforin, capable of mediating cytotoxicity. Typically, HIV specific CD8+ T cells from infected individuals, who have low viral loads are poly functional and can carry out most or all of these effectors functions [2]. Conversely, HIV-infected subjects with high viral loads often have HIV-specific CD8+ T cells , capable of only some of  normal effectors functions and, at  extreme of the spectrum, their dysfunctionality might be reflected by  expression of PD1 (programmed cell death 1),- a marker of T cell exhaustion. Proliferative capacity of both CD4+ and CD8+ T cells are also associated with control. In addition, genetic regulation of CCL3L1 (MIP-1aP) and CCR5 have been demonstrated to be important because they regulate CTL activity and other viral entry dependent mechanisms (3). By binding to CCR5 and promoting its sequestration, CCL3L1 can block HIV replication.

An apparently persistent suppression of viral replication coupled to no drop in CD4+ T cells occurs in about one of 300 persons infected with HIV (elite controllers). It is striking that, in a recent whole-genome association study of key determinants for host control of HIV-1,  six most significant protective determinants were within  MHC region. It is evident in HIV infection; HLA-B molecules have a stronger impact on viral set point than HLA-A and HLA-C. That gene,  HLA-B*5701, codes for a protein on immune cells that plays a central role in clearing the body of HIV-infected cells. The second implicated polymorphism is in HLA-C gene, which plays a similar role to HLA-B in mounting an effective immune response. A gag-specific but not env-specific CD8+ T-cell response was protective against disease progression[3]. Therefore, it is not just the number of Gag epitopes, presented by each allele that is important, but also  ability of the Gag-specific CD8+ T-cell response to drive the selection of escape mutations into less fit virus that have an impact on viral replication [5]. On other side, uncontrolled HIV replication cause non HIV specific immune activations and chronic inflammation , strongly associated with acquiring opportunistic cancers, chronic virus infections or Mycobacterium tuberculosis as well as end organ damage, including cardiovascular, hepatic and renal dysfunction.

Resistance to infection reflects some combination of genetic factors, innate resistance, and a probably very rare acquired immune control. Genetic studies  demonstrated that a deletion in the CCR5 gene (CCR5d32deletion) provides substantial protection from HIV-1 infection [4]. Members of the APOBEC (apo-lipoproteinB mRNA-editing catalytic polypeptide) family belong to cellular cytidine de-aminases that represent a recently identified group of proteins induced by IFNa that protect from infection by retroviruses [5]. Yet, HIV-1 is largely immune to  intrinsic antiviral effects of APOBEC proteins because it encodes a unique Vif gene(viral infectivity factor), an accessory protein that is critical for in vivo replication of HIV-1 due to VIF´s ability to inactivate APOBEC [6]. Another intercellular antiviral factor, the tripartite motif–containing 5-á (TRIM5-á) gene, inhibits  ability of different retroviruses to infect human and monkey cells by blocking virus capsid un coating [7]. HIV-1 infection is restricted by the old world monkey TRIM5-a gene, but not by the human counterpart explaining why HIV can infect CD4+ T cells [8]. Cellular miRNA can also interfere with HIV replication; however, HIV-1 can modify miRNA expression profiles in the infected cell (9). Several chemokines including, RANTES, MIP-1a/b and antimicrobial peptides such as a/b-defensins and LL 37 also inhibit HIV-1 replication locally. Thus, a number of innate mechanisms are of central importance for protection against HIV-1.Furthermore, neutralizing IgA in genital tract clearly contributes to protection against HIV-1. However, there are indications that these IgA antibodies are predominantly directed against host specific epitopes involved in virus binding and fusion, and it remains to be determined, if these are natural or of acquired origin.

To halt present pandemic, we authors do agree, a vaccine that protects from HIV-1 infection is urgently needed. An absolute worldwide commitment to this goal however established; Attempts to develop a protective vaccine have been severely compromised by our incomplete understanding of HIV-1 protective immunity. Further more, safe vaccine prototypes have so far failed to induce a sufficiently potent immune response against HIV-1 . RV144 vaccine, in October 2009, trial in Thailand showed a modest 31% efficacy in preventing HIV infection.

Other approaches may be with stem cells stitched with the anti-HIV genes into a high percentage of the appropriate stem cells, One example to cite for stem cells therapy with BMT. The story was like this published in journal Science in 2011, “Four years after Timothy Ray Brown received bone-marrow transplants to fight his leukemia, the most sophisticated labs in the world could not find any trace in his body of the HIV that had infected him for last 12 years. Brown is the only living human, a growing consensus contends, to be cured of HIV. Brown's treatment clearly does not offer a road map for many others. After all, the expensive, complex, and risky transplant only made sense because Brown was dying from leukemia. Nor is it clear exactly which components of the extensive transplant regimen cleared the virus from his body. But Brown's case has moved the much-ridiculed idea of curing HIV onto the most scientifically solid ground it has yet occupied, say leading AIDS researchers. Brown's case showed for the first time that it is possible to rid the body of the virus—even from the minuscule reservoirs where the virus can hide out for years, evading both the immune system and antiretroviral drugs (ARVs). His astonishing turn around also raised hopes that other, immune system modulators might find and destroy every last bit of virus—or at least reduce it to such low levels that people no longer need ARTs therapy [10].

 References

1] McCune, J.M. . The dynamics of CD4+ T-cell depletion in HIV disease. Nature. 410:974-979; 2001.

2] Miura T, Walker BD et al. Genetic characterization of human immunodeficiency virus type 1 in elite controllers: lack of gross genetic defects or common amino acid changes. J Virol. ;82(17):8422-30.;2008

3] Goulder PJ, Watkins DI. Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol. 8(8):619-30;2008

4] Stover, J., et al. The global impact of scaling up HIV/AIDS prevention programs in low- and middle income countries. Science. 311:1474-1476;2006

5] Ulenga NK, Sarr AD, Thakore-Meloni S, Sankalé JL, Eisen G, Kanki PJ. Relationship between humanimmunodeficiency type 1 infection and expression of human APOBEC3G and APOBEC3F. J Infect Dis. ;198(4):486-92.;2008

6] Goila-Gaur R, Strebel K. HIV-1 Vif, APOBEC, and intrinsic immunity. Retrovirology. 5:51-55;2008

7]. Sheehy, A.M., Gaddis, N.C., Chol, J.D., Malim, M.H. . Isolation of a human gene that inhibits HIV-1infection and is suppressed by the viral Vif protein. Nature. 418:646-650;2002.

8]Stremlau, M., et al. 2004. The cytoplasmic body component TRIM5a restricts HIV-1 infection in OldWorld monkeys. Nature. 427:848-853.

9]Kumar A, Jeang KT.Insights into cellular microRNAs and human immunodeficiency virus type 1 (HIV-1).J Cell Physiol. 216(2):327-31;2008.

10] Jon Cohen The Emerging Race to Cure HIV Infections Science 13 May 2011: Vol. 332 no. 6031 pp. 784-789 DOI: 10.1126/science.332.6031.784

Links to see other sites

http://www.nature.com/news/2010/100616/full/news.2010.301.html#comment-id-11383 at Nature News Published Cooments on Tripple punch Gene therapy in HIV

2]http://www.annals.org/content/148/10/792.extract/reply#annintmed_el_125040 at Annals of Internal Medicine

3]http://www.bmj.com/rapid-response/2011/11/01/sex-education-programme-teach-abstenism-safe-sex-had-very-little-impact-ad At BMJ Rapid response published asSex education programme that teach abstenism, safe sex had very little impact on adolescence behavior & role of Microbicide in prevention of HIV in Rich countries

4]http://www.bmj.com/rapid-response/2011/11/01/rapid-assay-tests-hiv1-or-vctc-which-plays-important-role-primary-health-c  in BMJ as rapid Response Rapid assay tests for HIV1 or VCTC which plays important role in Primary health care settings in West Bengal for surveillance, diagnosis & treatment of HIV1

5]http://www.bmj.com/rapid-response/2011/11/01/hiv-epidemic-ampnature-west-bengal-stateindia-role-male-circumcision-possi as rapid response HIV epidemic, &nature in West Bengal State;India,: Role of male Circumcision Possible amongst Hindus as additional preventive measure?Will state government start thinking of It?

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