Hiv why no vaccine

HIV transmission occurs mainly via the mucosa. The gut-associated lymphoid tissue system GALT is set up by activated B and T lymphocytes and dendritic cells which migrate through the lymphatic system and bloodstream to distant lymph nodes where they become resident. Thus, the induction of a strong immune response in mucosa is probably a necessary requirement for a vaccine to be efficient against HIV.

Each family of viruses develops different escape mechanisms to avoid elimination by the immune system. A vaccine must face the same escape mechanisms and, to be successful, must induce a series of immune responses capable of overcoming them.

The rate of variability of HIV is due to the high error rate of reverse transcriptase one substitution per 10 3 4 nucleotides and round of copy.

In consequence there is wide intersubtype and intrasubtype variability but the immunological relevance for vaccine design of this genetic disparity is a matter of debate. Several investigations have shown that genetic differences among HIV subtypes do not correlate with immunotypes.

In fact, several genetic subtypes could share common protective epitopes and more than one immunotype can be found in the same genetic subtype. In general, neutralizing antibodies seem to be more strain-specific, whereas cellular immune responses have a broader spectrum. This lack of fidelity generates a high diversity in viral proteins which allows escape from the control of specific immune response. Therefore, HIV shares with other RNA viruses a common escape mechanism related to their high variability that allow the virus finding holes in the immune repertoire.

Together with the variability generated by the high error rate of reverse transcriptase other mechanisms such as genetic recombination, which produces new subtypes and "mosaic" viruses among different subtypes, are also involved in the generation of HIV variants. Several molecular epidemiology studies have stressed the rapid dissemination of HIV variants and have described the distribution of several subtypes or recombinant viruses in different parts of the world.

This could be an obstacle to the development of a universal vaccine Mutations in the viral epitopes recognized by CTLs.

One central aspect of HIV infection which is not totally understood is the reason why viral replication is not controlled despite the potent immune responses elicited in primary infection. Although several explanations have been put forward, the most widely reported is viral escape through mutations in the viral epitopes recognized by the different effector mechanisms of the immune system Escape from CTL response is due to ad hoc mutations of the viral epitopes which interact with the groove of the HLA molecules.

It has been shown that mutations in critical residues generate viral escape in both animal models and patients with primary infection and this event results in loss in the CTL response and parallel increase in viremia 25, However, in the chronic phase of infection, there is no clear correlation between the presence of specific CTL and the elimination or persistence of a given viral variant In addition to merely quantitative data, functional analysis have shown qualitative differences between CTL from progressors and non-progressors, such as the expression of perforins 28 , production of cytokines and chemokines, and reduced activity of the T-cell receptor against viral epitopes presented in the HLA complex These data suggest that qualitative aspects of CTL may be also important in the control of viral replication.

A general strategy for maximizing the efficacy of a vaccine would be to obtain a cytotoxic response against a large number of epitopes from several proteins. However, recent studies suggest that a more targeted approach can be more effective. Thus, CTL against non-structural proteins Tat, Nef are more efficient in controlling infection but more prone to viral escape and do not last as long as CTL against the structural proteins Gag and Pol For a sterilizing vaccine, the objective would be to induce an intense CTL response against early proteins, whereas immunization against structural proteins would generate a response which would control viral replication thus attenuating infection.

Another problem which may be a serious genetic resistance barrier is the adaptation of the virus to the HLA haplotype of the infected patient. In this situation peptides from viral mutants generated would reduce their affinity to HLA thus decreasing recognition by TcR and generating a greater resistance to CTL response Biochemical characteristics of the viral envelope and escape from antibody action.

The structure of the viral envelope in its native form hides the domains of interaction with viral coreceptors due to the trimeric structure and folding of the protein oligomeric exclusion and entropic masking Exposure of these conserved epitopes which are identified by neutralizing antibodies takes place at the moment of interaction between the viral and cellular membranes, a setting in which antibodies efficacy is lower given their low accessibility to neutralization epitopes.

A second, more classic escape mechanism is epitopic mutation in the hypervariable regions found in the external domain of the viral envelope. Nevertheless, recent studies show that escape from these antibodies does not always require mutation in amino acid residues but takes place by glycosylation of the residues and formation of carbohydrate structures on viral gp known as "glycan shields" that represent authentic barriers to the action of neutralizing antibodies One of the most spectacular studies published during the last year shows how, during evolution in a specific patient, the viral envelopes gradually become resistant to all types of neutralization by neutralizing antibodies via accumulation of the previously mentioned escape mechanisms Early establishment of infection.

Both in animal models and in patients with primary infection through sexual contact the establishment of HIV infection is a very rapid process In a few hours, the lymphoid cells of the rectal and vaginal submucosa become infected and, in seven days, the infection spreads to systemic lymph nodes where it reaches viral and proviral loads similar to levels found in chronic infection The speed at which these reservoirs appear, before a specific immune response is triggered, represents a major obstacle to the control of viral replication since once established HIV infection will "persists" in lymphocytes despite immune response HIV can infect target cells in a latent form.

In this situation no viral proteins are expressed on the membrane of infected cells thus allowing escape from immune surveillance. Furthermore, reactivation-reinfection processes take place in lymphoid organs, which provide an ideal cellular microenvironment for the process of infection: dendritic cells express in their membrane a lectin DC-SIGN which interacts with the virions and lymphocytes and enhances HIV infection Antigenic recognition by lymphocytes and the presence of cytokines in this microenvironment in turn increase infection of target cells and promote viral replication.

As confirmation of these data, HIV-specific lymphocyte clones have been shown to be infected at higher proportion, which implies a preferential immunosuppression of the HIV-specific responses It must be stressed that the continuous generation of new, latently infected cells from the active viral replication compartment generates a "continuous archive" of changes produced in the virus throughout the disease, by including treatment-resistant mutated genomes and variants of the immune escape.

The latent compartment is therefore not static and in some way HIV stores its "history" in latently infected cells 32 thus contributing to viral diversity as a mechanism of escape from antiretroviral therapy and vaccines. Prototype HIV vaccines. Experimental results. Attenuated virus vaccines are without doubt the most efficacious because the germ carries out a limited series of replication cycles and simulates a low-level infection which induces the whole spectrum of antiviral response in a physiological setting.

In the case of lentiviruses, one of the most spectacular findings was that which showed that a defective Nef-deleted SIV virus induced a protective response against the challenge with highly pathogenic aggressive viable viruses These experimental data had a natural correlate in the "Sydney Cohort", made up of 14 patients infected through blood transfusion from a seropositive donor and who, after 12 years of infection, had an excellent clinical and immunological status.

The cloning and characterization of the virus in these patients and the donor showed that it presented deletions in the Nef gene and in critical regulatory sequences of the LTR region However, it must be stressed that attenuated vaccines are usually used against viruses which do not persist or, alternatively, the attenuated virus used as vaccine is not capable of persisting in the host.

This is not the case for Nef-defective viruses which not only infect, but also replicate and persist in the host, with the risk of drifting towards more aggressive variants in the vaccinated subject. The first alarming data came from vaccination of newborn macaques in which, in contrast with was found in adults, the innocuous virus rapidly induced aggressive infection and death by immunodeficiency Furthermore, prolonged follow-up of patients from the Sydney cohort enabled us to observe an immunological deterioration and blips of viremia in some subjects Similarly, some adult macaques vaccinated with the defective SIV virus developed aids from the virus they had been vaccinated with, which suffered reversions of the mutant phenotype Therefore, the use of vaccines from defective viruses has been ruled out, and this approach has been explicitly excluded in guidelines and recommendations of regulatory agencies.

Inactivated viruses have scarcely been used as preventive vaccines. These viral preparations are composed of complete virions or particles whose envelope has been eliminated, which are then inactivated using different chemical methods and administered in conjunction with Freund's incomplete adjuvant The first HIV vaccines were based on the hepatitis B immunization model.

They were composed of recombinant proteins gp and gp produced by genetic engineering or using vaccinia virus as expression vectors. In pre-clinical studies and in phase I and phase II clinical trials, the preparation was safe and induced antibody synthesis against the viral envelope 44 , but these antibodies were incapable of neutralizing wild-type variants "in vitro" In spite of the evidence against the efficacy of this prototype, phase III trials were continued see below.

Other trials have used the regulatory protein tat in toxoid form, which has provided good protection results in macaque studies, although its role remains controversial Peptide vaccines have little immunogenic capacity, since, in many cases, the antibodies do not recognize the primary structure of the aminoacid sequence, but rather secondary and tertiary structures in the target proteins which are not simulated by the peptides. Therefore, peptides are generally used in combination with other vaccine preparations such as viral vectors or DNA in order to induce complementary immunization The advantages of these combinations are low toxicity, the possibility of preparing peptide "cocktails" which cover a wide range of viral isolates in proteins presenting high variability, and the use of "mixed peptides" which, by including T and B immunodominant epitopes induce cellular and humoral responses.

Bacterial and viral vectors live-attenuated. These systems use viruses or bacteria into whose genome HIV genes are inserted in such a way that their proteins are expressed during the course of replication of the vectors in the host cell. Some of these systems are limited by the risk that exogenous genetic information from the vector can be integrated in the host genome. The advantage of these viral and bacterial systems lies in the possibility of inserting several viral genes in their genomes and their capacity to express high levels of viral proteins.

Strong antigen expression can in turn induce a potent and prolonged immune stimulation, particularly of cellular immune responses, against these proteins.

The vaccine prototypes currently being developed include the genes gag, pol, env and nef in different combinations 48,49 , different priming-boosting strategies and vaccine doses. These types of preparation have failed as preventive vaccines in animal models, since they have not achieved protective immunity, probably due to the fact that the humoral response induced against HIV proteins is erratic and of reduced potency.

They do, however, induce a potent cellular response which makes viral load stabilize at low levels 48, In the most optimistic scenario it has been suggested that this response could be enough to "attenuate" the infection and transforming vaccinated patients who become infected into "long-term survivors".

DOI: Moody, M. J Virol. Rubens, M. J Immunol Res. Schoofs, T. Your Privacy Rights. To change or withdraw your consent choices for VerywellHealth. At any time, you can update your settings through the "EU Privacy" link at the bottom of any page. These choices will be signaled globally to our partners and will not affect browsing data. We and our partners process data to: Actively scan device characteristics for identification. I Accept Show Purposes. Why is there no vaccine for HIV?

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Related Articles. Is HIV Curable? How Therapeutic Vaccines Work. Based on these promising results, a larger follow-up study called HVTN is now underway. Many people are hopeful that it will lead to our first HIV vaccine. Results are expected in This trial of a prophylactic vaccine studies people in:. The trial adopts a live vector vaccine strategy, using the Sendai virus to carry HIV genes. Data collection from this study is complete.

This means the immune response would target all HIV strains. Most other vaccines only target one strain. The study ended in , and results are expected soon. And to date, more than 40 potential vaccines have been tested. But with each failure, more is learned that can be used in new attempts.

For answers to questions about an HIV vaccine or information on taking part in a clinical trial, a healthcare provider is the best place to start. They can answer questions and provide details about any clinical trials that might be a good fit. Read this article in Spanish.

Jahlove is an HIV prevention advocate. He guides us through discussions with resources across the country who work to improve people's access to PrEP. Learn how to have a safe and healthy relationship with a partner who has HIV.

Get the facts on helping a partner manage their HIV, medications that…. Discover the best time to be tested for HIV. Discussing HIV-related issues can be difficult or uncomfortable to bring up. These properties have important consequences relevant for vaccine development efforts.

The antibodies that an HIV-infected person makes typically have only very weak neutralizing activity against the virus. Furthermore, these antibodies are very strain-specific; they will neutralize the strain with which the individual is infected but not the thousands and thousands of other strains circulating in the population. Researchers know how to elicit antibodies that will neutralize one strain, but not antibodies with an ability to protect against the thousands and thousands of strains circulating in the population.

HIV is continually evolving within a single infected individual to stay one step ahead of the immune responses. The host elicits a particular immune response that attacks the virus. The result is continuous unrelenting viral replication. So, should we researchers give up? One approach researchers are trying in animal models in a couple of laboratories is to use herpes viruses as vectors to deliver the AIDS virus proteins. Once infected with a herpes virus, you are infected for life.

And immune responses persist not just as memory but in a continually active fashion. Success of this approach, however, will still depend on figuring out how to elicit the breadth of immune responses that will allow coverage against the vast complexity of HIV sequences circulating in the population. Another approach is to go after protective immunity from a different angle. Although the vast majority of HIV-infected individuals make antibodies with weak, strain-specific neutralizing activity, some rare individuals do make antibodies with potent neutralizing activity against a broad range of HIV isolates.