HIV does induce an immune response against itself in the infected host. The problem is statement 1, where the high mutational rate of the virus ensures escape from the specific immune response that the specific host elicits. 

A vaccine also induces an immune response that does not provide a protective immunity, unfortunately. 

Hello Sanath and thank you for your kind reply,

yes for your first paragraph a great analogy that I read was 'an immune response against an infected individual is similar to a local firehouse being on fire!'

for your second reply I am assuming that it does not provide protective immunity again because of the high mutation rate, correct?

Thanks Joel for the excellent question, which I think touches on a few perceived wisdoms about HIV vaccines and vaccination in general.

1) Mutation rate: This is commonly cited as a reason why it is difficult to create a vaccine which establishes long-lasting protective immunity to HIV. So what about mutation rates in other RNA viruses for which there are effective vaccines? In the attached paper Fig 4 puts the mutation rate of the retroviridae in a similar ball park to the paramyxoviridae, orthomyxoviridae, picornaviridae and the hepadnaviridae, families which contain viral species for which we have developed effective vaccines. I think with more recent methods HIV-1, specifically, does have a higher mutation rate, compared to other RNA viruses, but this is mainly driven by host A3 cytidine deaminases (see link to paper below), which are packaged in the virion and upon infection, mediate cytidine to uracil editing in the viral cDNA, resulting in G-A mutations in viral genomic RNA. In long term non-progressors you see higher mutation rates, compared with more rapid processors, where the virus is more stable, maybe reflecting genetic differences in host factors such as A3 cytidine deaminases. I would say mutation is a factor... but not the whole story in why it is difficult to immunise against HIV-1.

http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002251

2) Latency: When you look at viral infections for which there are effective vaccines (e.g.. measles, polio, mumps, rubella, small pox, yellow fever..) they are almost exclusively viral infections for which wild-type infection induces long-lasting protective immunity. A possible exception to this is varicella zoster, but whilst this does establish latency, reactivation is rare in the absence of severe immunosuppression. Other latent pathogens, such as HIV-1 & 2, Tuberculosis and Malaria, the development of effective vaccines ha been extremely challenging. The BCG vaccine is broadly ineffective against pulmonary TB (most new TB cases are in vaccinated individuals), but is still used because it appears to protect against severe TB meningitis in children, and more broadly, because it's ethically almost impossible to remove a vaccine once you've started using it.

3) Attenuation: Most effective vaccines are live-attenuated, meaning that they actually cause a low level infection within the vaccinated individual, stimulating across the spectrum of the immune repose (innate + adaptive, humoral + cellular). Developing attenuated HIV is a no-go for obvious reasons and so the main focus has been on sub-unit vaccines... but when wild-type infection, presenting all possible antigens to the immune system, doesn't induce lasting immunity, it seems unlikely that the presentation of just a couple of antigens will do so. A recent sub-unit vaccine trial on TB was a massive flop, despite years of careful work-up. For HIV there is maybe a little more hope, with some positives for the RV144 trial, but even if you achieve, say, 30% protection, I feel that complimentary strategies like antibody or drug prophylaxis are going to be an important component of the fight against HIV moving forward, along with continued and relentless efforts to reduce stigma, encourage safe behaviour + economic empowerment.

Hi Mat and thank you for your kind reply,

my inference from your above answer is that vaccines towards HIV are arduous simply due to HIVs high mutation rate resulting in high antigenic variability.  However, I thought there was something more besides this, I thought there is a cloaking involved with HIV's antigens resembling the hosts own antigens?  Insights?

Thanks:)

Joel

Yes, I think cloaking is also a well-established phenomenon:

"The higher frequencies of autoreactivity and/or polyreactivity among HIV-1 bnAbs (Liu et al., 2015) suggest that conserved, neutralizing epitopes present on the HIV-1 Env may have been selected to resemble host determinants (Haynes et al., 2005; Haynes et al., 2012b; Yang et al., 2013). Studies of knock-in mice that express the V(D)J rearrangements of human bnAbs or their germline ancestors (Chen et al., 2013; Doyle-Cooper et al., 2013; Verkoczy et al., 2011; Verkoczy et al., 2010), and the identification of host antigens that structurally resemble or are identical to HIV-1 determinants, both support this hypothesis (Liu et al., 2015; Yang et al., 2013). Thus, a key hypothesis pursued by our group is that HIV-1 infection induces immune perturbations that relax immune tolerance controls and eventually promote the expression of bnAbs with traits of antibodies normally disfavored by immune tolerance mechanisms (Haynes and Verkoczy, 2014)."

An excerpt from

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823811/

Aloha and thanks a bunch for the affirmation/details:)

Best,

Joel

The first part of Matthew's answer, although true, does not really represent the clinical situation very well. Mutation rates are high in all viruses that utilize RNA-dependent RNA polymerases, but the mutation rate itself doesn't explain what is really going on.

For example, RSV has a high mutation rate but virtually all mutants are at a significant selective disadvantage; therefore, RSV isolates that are circulating right now do not differ substantially from the very first RSV that was discovered in 1956. In other words, the mutation rate does not translate into spread of mutant viruses.

Influenza has a similar mutation rate; unfortunately, in this case, many mutants actually develop a survival advantage because of herd immunity against the pre-mutation strains. For this reason, control of influenza with vaccination is difficult, and vaccination has to be repeated each year.

The issue with mutation in HIV is that, although some mutations definitively decrease viral fitness, not all do; therefore, mutant viruses can be spread from person-to-person. [Also because the numbers of circulating virus can be extremely high (on the order of 8-10 million virions/mL of plasma in some cases), the same mutation rate as other viruses still results in a lot more circulating mutant viruses.] For a vaccine to be completely protective it would thus have to be able to provide immunity against all the circulating mutants.

The third part of Matthew's answer is also not factual. Some subunit vaccines are among the most effective vaccines ever developed. Invasive H. flu type b infections have virtually disappeared because of a subunit vaccine. Hepatitis B virus vaccine is upwards of 98% protective, and it, too, is a subunit vaccine.

It is simply not accurate to state that the majority of effective vaccines are attenuated vaccines.

Hello and thank you Randall for your kind reply and info.:)

From the most fundamental standpoint, efforts to develop an HIV vaccine have been hampered by the genetic diversity of the virus itself. The replication cycle of HIV is not only fast (a little more than 24 hours) but is prone to frequent errors, churning out mutated copies of itself which recombine into new strains as the virus is passed from person to person. Developing a single vaccine able to eradicate over 60 dominants strains as well as the multitude of recombinant strains—and on a global level—becomes all the more challenging when conventional vaccines can only protect against a limited number of viral strains.

Secondly, fighting HIV demands a robust response from the immune system, and this again where systems fail. Traditionally, specialized white blood cells called CD4 T-cells initiate the response by signaling killer cells to the site of the infection. Ironically, these are the very cells that HIV targets for infection. By doing so, HIV hobbles the body’s ability to defend itself as the CD4 population is systematically depleted, resulting in the eventual breakdown of defenses called immune exhaustion.

Finally, the eradication of HIV is thwarted by the virus’ ability to hide from the body’s immune defenses. Soon after infection, while other HIV is circulating freely in the bloodstream, a subset of virus (called provirus) embeds itself in hidden cellular sanctuaries (called latent reservoirs). Once inside these cells, HIV is shielded from detection.

Joel Subach a diversity experimental HIV vaccines could provoke an anti-HIV immune response, but it was insufficient to lead to protection in participants. The quality of induced immune response was, again and again, dissapointing.

After decades of research and many failed trials, HIV vaccine research recognized enormous importance of stimulation of human immune system to create rare but powerful anti-HIV antibodies, called broadly neutralizing antibodies (bNabs). They can neutralize diverse strains of HIV.

But unlike other vaccines –most of them work by inducing the B-cells of the immune system to make antibodies against the infection that the vaccine mimics, HIV-vaccine would need to have specific features. In vast majority of HIV positive humans, anti-HIV antibodies don’t work efficiently. In very few HIV-infected individuals, broadly neutralizing anti-HIV immune globulins can be synthesized. We can try to understand and mimic the immune response, seen in rare HIV elite controllers, and use exactly this principle in development of HIV vaccine.

The bNabs can overcome the tremendous genetic variability of HIV and the ‘glycan shielding’ seen in HIV (HIV shields its Env-protein using glycans). bNabs have favorable extensions to normal anti HIV-immunoglobulin molecules, that enable them to penetrate the glycan shield and find the critical epitopes on HIV despite of glycan shielding effect. This is of huge importance, since HIV can not afford to mutate this epitopes- if this occurs, the fitness of HIV is insufficient to continue the viral cycles.

Such bNab generating HIV-vaccines could indeed be the game changer. But to realize them, we have to overcome huge challenges. One of them is clearly the rarity of desired cells: approximately 1 in about 300 000 B-cells had the capability to synthesize the potent bNabs.

I had a privilege to experiment with few bNab-generating strategies. However, the research is limited by lacking suitable techniques and of course sponsoring ( and self-sponzoring means a huge burden), and currently the SARS-CoV-2 crisis is disadvantageous , without any doubt. Currently , i m involved in a time consuming drug descovery project. So, taken together it will take time.

Best regards and good luck :)

Hello Drazen and thank you for your kind and very informative update:).

Best,

Joel