Editing HIV vaccine development (section)

==Difficulties in development==
In 1984, after it was confirmed that HIV caused AIDS, the United States [[Health and Human Services Secretary]] [[Margaret Heckler]] declared that a [[vaccine]] would be available within two years.<ref>{{cite book | last = Shilts | first = Randy | year = 1987 | title = And the Band Played On: Politics, People, and the AIDS Epidemic | edition = 2007 | publisher = St. Martin's Press | isbn = 978-0-312-24135-3 | page = [https://archive.org/details/andbandplayedonp00shil_0/page/451 451] | url-access = registration | url = https://archive.org/details/andbandplayedonp00shil_0/page/451 }}</ref> However, priming the [[adaptive immunity|adaptive immune]] system to recognize the [[viral envelope]] proteins did not prevent HIV acquisition.

Many factors make the development of an HIV vaccine different from other classic vaccines (as of 1996):<ref>{{cite journal | vauthors = Fauci AS | year = 1996 | title = An HIV vaccine: breaking the paradigms | journal = Proc. Am. Assoc. Phys. | volume = 108 | issue = 1| pages = 6–13 | pmid = 8834058 }}</ref>
* Classic vaccines mimic natural immunity against reinfection as seen in individuals recovered from infection; there are few recovered AIDS patients.
* Most vaccines protect against disease, not against infection; HIV infection may remain latent for long periods before causing AIDS.
* Most effective vaccines are whole-killed or live-attenuated organisms; killed HIV-1 does not retain antigenicity and the use of a live retrovirus vaccine raises safety issues.

===HIV structure===
[[File:Hiv gross.png|thumb|HIV structure cycle]]
The [[epitope]]s of the viral envelope are more variable than those of many other viruses. Furthermore, the functionally important epitopes of the [[gp120]] protein are masked by [[glycosylation]], [[trimerisation]] and receptor-induced conformational changes making it difficult to block with neutralizing antibodies.

The ineffectiveness of previously developed vaccines primarily stems from two related factors:
* First, HIV is highly mutable. Because of the virus's ability to rapidly respond to selective pressures imposed by the immune system, the population of virus in an infected individual typically evolves so that it can evade the two major arms of the adaptive immune system; humoral ([[antibody]]-mediated) and cellular (mediated by [[T cells]]) immunity.
* Second, HIV isolates are themselves highly variable. HIV can be categorized into multiple subtypes with a high degree of genetic divergence. Therefore, the immune responses raised by any vaccine need to be broad enough to account for this variability. Any vaccine that lacks this breadth is unlikely to be effective.

The difficulties in stimulating a reliable [[antibody]] response has led to the attempts to develop a vaccine that stimulates a response by [[cytotoxic T-lymphocyte]]s.<ref name="pmid17502236">{{cite journal | vauthors = Kim D, Elizaga M, Duerr A | title = HIV vaccine efficacy trials: towards the future of HIV prevention | journal = Infectious Disease Clinics of North America | volume = 21 | issue = 1 | pages = 201–17, x | date = March 2007 | pmid = 17502236 | doi = 10.1016/j.idc.2007.01.006 }}</ref><ref name="pmid18425263">{{cite journal | vauthors = Watkins DI | title = The hope for an HIV vaccine based on induction of CD8+ T lymphocytes--a review | journal = Memórias do Instituto Oswaldo Cruz | volume = 103 | issue = 2 | pages = 119–29 | date = March 2008 | pmid = 18425263 | pmc = 2997999 | doi = 10.1590/S0074-02762008000200001 }}</ref>

Another response to the challenge has been to create a single peptide that contains the least variable components of all the known HIV strains.<ref name="pmid17912361">{{cite journal | vauthors = Létourneau S, Im EJ, Mashishi T, Brereton C, Bridgeman A, Yang H, Dorrell L, Dong T, Korber B, McMichael AJ, Hanke T | title = Design and pre-clinical evaluation of a universal HIV-1 vaccine | journal = PLOS ONE | volume = 2 | issue = 10 | pages = e984 | date = October 2007 | pmid = 17912361 | pmc = 1991584 | doi = 10.1371/journal.pone.0000984 | editor1-last = Nixon | editor1-first = Douglas | bibcode = 2007PLoSO...2..984L | doi-access = free }}</ref>

It had been observed that a few, but not all, HIV-infected individuals naturally produce [[Broadly neutralizing HIV-1 antibodies|broadly neutralizing antibodies]] (BNAbs) which keep the virus suppressed, and these people [[Long-term nonprogressor|remain asymptomatic for decades]]. Since the 2010s a core candidate is VRC01 and similar BNAbs, as they have been found in multiple unrelated people.<ref>{{cite journal |last1=West AP |first1=Jr |last2=Diskin |first2=R |last3=Nussenzweig |first3=MC |last4=Bjorkman |first4=PJ |title=Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120. |journal=Proceedings of the National Academy of Sciences of the United States of America |date=24 July 2012 |volume=109 |issue=30 |pages=E2083-90 |doi=10.1073/pnas.1208984109 |pmid=22745174|pmc=3409792 |doi-access=free |bibcode=2012PNAS..109E2083W }}</ref> These antibodies mimic CD4 and compete for the conserved CD4 binding site. These antibodies all share a [[germline]] origin in the [[Immunoglobulin heavy chain|V<sub>H</sub> chain]], where only a few human [[allele]]s of the IVIG1-2 gene are able to produce such an antibody.<ref name=pmid34489473>{{cite journal |last1=Lee |first1=Jeong Hyun |last2=Toy |first2=Laura |last3=Kos |first3=Justin T. |last4=Safonova |first4=Yana |last5=Schief |first5=William R. |last6=Havenar-Daughton |first6=Colin |last7=Watson |first7=Corey T. |last8=Crotty |first8=Shane |title=Vaccine genetics of IGHV1-2 VRC01-class broadly neutralizing antibody precursor naïve human B cells |journal=npj Vaccines |date=6 September 2021 |volume=6 |issue=1 |page=113 |doi=10.1038/s41541-021-00376-7 |pmid=34489473|pmc=8421370 |doi-access=free }}</ref> Env is a protein on the HIV surface that enables to infect cells. Env extends from the surface of the HIV virus particle. The spike-shaped protein is "trimeric" — with 3 identical molecules, each with a cap-like region called glycoprotein 120 (gp120) and a stem called glycoprotein 41 (gp41) that anchors Env in the viral membrane. Only the functional portions of Env remain constant, but these are generally hidden from the immune system by the molecule's structure. X-ray analyses and low-resolution electron microscopy have revealed the overall architecture and some critical features of Env. But higher resolution imaging of the overall protein structure has been elusive because of its complex, delicate structure. Three new papers use stabilized forms of Env to gain a clearer picture of the intact trimer. An NCI research team led by Dr. Sriram Subramaniam used cryo-electron microscopy to examine the Env structure. The study appeared on October 23, 2013, in ''Nature Structural and Molecular Biology''.<ref>{{Cite web |date=2015-05-14 |title=Key HIV Protein Structure Revealed |url=https://www.nih.gov/news-events/nih-research-matters/key-hiv-protein-structure-revealed |access-date=2023-01-05 |website=National Institutes of Health (NIH) |language=EN}}{{PD-notice}}</ref>

===Animal model===
[[File:2006-12-09 Chipanzees D Bruyere.JPG|thumb| Young chimpanzees from [[Tchimpounga Sanctuary]] ([[Republic of the Congo]])]]
The typical [[animal model]] for vaccine research is the monkey, often the [[macaque]]. Monkeys can be infected with [[Simian immunodeficiency virus|SIV]] or the chimeric SHIV for research purposes. However, the well-proven route of trying to induce neutralizing antibodies by vaccination has stalled because of the great difficulty in stimulating antibodies that neutralise heterologous primary HIV isolates.<ref>{{cite journal | vauthors = Poignard P, Sabbe R, Picchio GR, Wang M, Gulizia RJ, Katinger H, Parren PW, Mosier DE, Burton DR | display-authors = 6 | title = Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo | journal = Immunity | volume = 10 | issue = 4 | pages = 431–8 | date = April 1999 | pmid = 10229186 | doi = 10.1016/S1074-7613(00)80043-6 | doi-access = free }}</ref> Some vaccines based on the virus envelope have protected chimpanzees or macaques from homologous virus challenge,<ref>{{cite journal | vauthors = Berman PW, Gregory TJ, Riddle L, Nakamura GR, Champe MA, Porter JP, Wurm FM, Hershberg RD, Cobb EK, Eichberg JW | display-authors = 6 | title = Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gp120 but not gp160 | journal = Nature | volume = 345 | issue = 6276 | pages = 622–5 | date = June 1990 | pmid = 2190095 | doi = 10.1038/345622a0 | bibcode = 1990Natur.345..622B | s2cid = 4258128 | doi-access = free }}</ref> but in clinical trials, humans who were immunised with similar constructs became infected after later exposure to HIV-1.<ref>{{cite journal | vauthors = Connor RI, Korber BT, Graham BS, Hahn BH, Ho DD, Walker BD, Neumann AU, Vermund SH, Mestecky J, Jackson S, Fenamore E, Cao Y, Gao F, Kalams S, Kunstman KJ, McDonald D, McWilliams N, Trkola A, Moore JP, Wolinsky SM | display-authors = 6 | title = Immunological and virological analyses of persons infected by human immunodeficiency virus type 1 while participating in trials of recombinant gp120 subunit vaccines | journal = Journal of Virology | volume = 72 | issue = 2 | pages = 1552–76 | date = February 1998 | pmid = 9445059 | pmc = 124637 | doi =  10.1128/JVI.72.2.1552-1576.1998}}</ref>

There are some differences between SIV and HIV that may introduce challenges in the use of an animal model. The animal model can be extremely useful but at times controversial.<ref>{{cite journal | vauthors = Morgan C, Marthas M, Miller C, Duerr A, Cheng-Mayer C, Desrosiers R, Flores J, Haigwood N, Hu SL, Johnson RP, Lifson J, Montefiori D, Moore J, Robert-Guroff M, Robinson H, Self S, Corey L | display-authors = 6 | title = The use of nonhuman primate models in HIV vaccine development | journal = PLOS Medicine | volume = 5 | issue = 8 | pages = e173 | date = August 2008 | pmid = 18700814 | pmc = 2504486 | doi = 10.1371/journal.pmed.0050173 | author-link8 = Nancy Haigwood | doi-access = free }}</ref>

There is a new animal model strongly resembling that of HIV in humans. Generalized immune activation as a direct result of activated CD4+ T cell killing - performed in mice allows new ways of testing HIV behaviour.<ref>{{cite journal | vauthors = Marques R, Williams A, Eksmond U, Wullaert A, Killeen N, Pasparakis M, Kioussis D, Kassiotis G | display-authors = 6 | title = Generalized immune activation as a direct result of activated CD4+ T cell killing | journal = Journal of Biology | volume = 8 | issue = 10 | page = 93 | year = 2009 | pmid = 19943952 | pmc = 2790834 | doi = 10.1186/jbiol194 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Vrisekoop N, Mandl JN, Germain RN | title = Life and death as a T lymphocyte: from immune protection to HIV pathogenesis | journal = Journal of Biology | volume = 8 | issue = 10 | page = 91 | year = 2009 | pmid = 19951397 | pmc = 2790836 | doi = 10.1186/jbiol198 | doi-access = free }}</ref>

[[National Institute of Allergy and Infectious Diseases|NIAID]]-funded SIV research has shown that challenging monkeys with a [[cytomegalovirus]] (CMV)-based SIV vaccine results in containment of virus. Typically, virus replication and dissemination occurs within days after infection, whereas vaccine-induced T cell activation and recruitment to sites of viral replication take weeks. Researchers hypothesized that vaccines designed to maintain activated effector memory T cells might impair viral replication at its earliest stage.{{Citation needed|date=October 2012}}

Specific vaccines may also need specialized animal models. For example, vaccines designed to produce VRC01-type antibodies require human-like V<sub>H</sub> alleles to be present. For organisms like mice, the human allele must be inserted into their genome to produce a useful mimic.<ref>{{cite journal |last1=Lin |first1=YR |last2=Parks |first2=KR |last3=Weidle |first3=C |last4=Naidu |first4=AS |last5=Khechaduri |first5=A |last6=Riker |first6=AO |last7=Takushi |first7=B |last8=Chun |first8=JH |last9=Borst |first9=AJ |last10=Veesler |first10=D |last11=Stuart |first11=A |last12=Agrawal |first12=P |last13=Gray |first13=M |last14=Pancera |first14=M |last15=Huang |first15=PS |last16=Stamatatos |first16=L |title=HIV-1 VRC01 Germline-Targeting Immunogens Select Distinct Epitope-Specific B Cell Receptors. |journal=Immunity |date=13 October 2020 |volume=53 |issue=4 |pages=840–851.e6 |doi=10.1016/j.immuni.2020.09.007 |pmid=33053332|pmc=7735217 |doi-access=free }}</ref> Murines are also experimental animals in AIDS and also murine AIDS and human AIDS are similar. Immunological analysis and genetic studies reveal resistant gene(s) in the H-2 complex of mice, an indication that genetic differences in mice could modify features of HIV disease. The defective murine leukemia virus is the major etiologic agent of MAIDS, which seems to be able to induce disease in the absence of virus replication. Target cell proliferation and oligoclonal expansion are induced by the virus, which suggests repressed immunity seen in mice thus referred to as paraneoplastic syndrome. This is further supported by the good response(s) of MAIDS mice to antineoplastic agents. This animal model is useful in demonstrating the emergence of novel hypotheses about AIDS, including the roles of defective HIV and HIV replication in the progression of the disease, and also the importance of identifying the HIV targeted cells ''in vivo.''<ref>{{Cite book |last1=Ibeh |first1=Bartholomew Okechukwu |url= |title=Experimental Animal Models of HIV/AIDS for Vaccine Trials |last2=Ashano |first2=Efejiro |date=2018-11-05 |publisher=IntechOpen |isbn=978-1-78923-165-6 |language=en }}</ref>