Editing HIV vaccine development (section)

===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>