Over the years, researchers have taken a number of approaches to developing HIV vaccines, using different molecular targets including:

1. Subunits of the virus: By training the immune system to target the sticky glycoprotein “spines” on the surface of the HIV envelope, a patient might be immunized by exposing them to just pieces of the intact virus – a safer strategy than using inactive forms of the complete virus⁶³. However, this approach is impeded because the body does not seem to respond equally to free-floating and envelope-embedded forms of these glycoproteins.
2. Hybrid viruses: By fusing components of HIV into a non-HIV pathogen (such as poxvirus or salmonella), the immune system can be trained to recognize HIV components on a different virus⁶⁴. Clearly, one disadvantage of this approach is that the recombinant virus can itself cause disease in the host. Further, if the patient has already been immunized against the virus used to house the foreign HIV particles, than the vaccine probably will not work because the body is already trained to destroy the very system used to introduce HIV particles. The immune system thus never gets a chance to “train” itself on the HIV components.

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3. Live, inactivated HIV: The most effective vaccines thus far use live HIV that is inactive; this clearly has safety concerns, but fail-safes can be incorporated into the viral genome that, for example, make the live strain more susceptible to antiviral compounds.

Reshuffling the viral deck: Resistance to drugs and vaccines

However, despite over a decade of research, an actual cure remains an unmet challenge in the battle against AIDS. Many factors make vaccine and drug development difficult, including the virus’ rapid replication rate ⁶⁰. Compared to the replication of the human genome during cell division, RNA viruses, like HIV, copy their genetic material in an extremely error-prone manner. In fact, it is faulty enough that one mutation can occur each time the virus replicates⁶⁶. One mutation may not seem like much, but since HIV can produce 1-10 billion new virions a day, favorable mutations aren’t very hard to achieve statistically in its small genome⁶⁷. In fact, these numbers mean that every base pair in the viral genome can be mutated in a day. Further, any treatment can exert selective pressure on the viral population, pruning away weaker variants and leaving only the hardiest viruses left over to replicate further⁶⁷. Given all of this, it’s easy to see that making a vaccine or drug would be difficult, since HIV’s genetic code is so inherently unstable.

A second impediment to vaccine development, similar to mutation, is that different HIV strains can recombine to further increase the variability of their genetic makeup^60,68. This happens because HIV, unlike other viruses, has two copies of its RNA genome⁶⁹. Normally they are identical, but if a cell is infected simultaneously by more than one HIV, then some virions can actually inherit two RNA strands that originally come from different viruses. When these recombined viruses then replicate, their reverse transcriptase can skip between the two strands when making its DNA copy, allowing genetic sequences from two viruses to be recombined into a single strand⁷⁰. Since antibodies are usually specific to a given genetic sequence, either source of variation can quickly eliminate the single site to which an antibody would bind, rendering a vaccine useless.

Another obstacle is that scientists still do not fully understand what kind of immune responses might limit the virus’ growth. Clearly, one way to answer this question might be to study immune responses in individuals who remain HIV-negative even after being exposed to the virus many times (see more on this below)⁶⁰. However, even in these cases it is often unclear whether these immune responses are actually preventing infection or if they are the left-over reactions to viral infections that did not take hold⁶⁰. In other words, it’s hard to know whether the virus failed to successfully infect the body, or the immune system actively prevented it from doing so. Additionally, the fact that the virus can integrate itself into its host cell’s genome (where it consists of just a DNA sequence, without translated protein) means that it can avoid antibodies directed at viral proteins⁶⁰. As mentioned above, the virus is invisible in this form to the immune system⁶⁰.

Natural Immunity?

A glimmer of hope in the effort to develop an HIV vaccine came with the discovery of a group of prostitutes in Nairobi, Kenya, who, despite repeated exposure to HIV through their work remained uninfected⁷¹. Scientists guessed that this was due to a large number of “anti-HIV” immune cells stimulated by repeated exposure to the virus⁷¹. Thus, trials began to develop “multi-vaccine” treatments that mimicked repeated exposure to HIV by “boosting” the initial vaccine with a second injection at a later date⁷². However, the ultimate results in clinical trails reported in 2004 proved disappointing⁷³. Additionally, some of these immune prostitutes have developed AIDS upon leaving the sex-trade industry, leading to further uncertainty about this phenomenon^71-73.

Comprehension Questions:
1. What makes an antiretroviral different from a vaccine?
2. What is one way in which an antiretroviral compound can inhibit HIV, on the molecular level?
3. What components of the HIV virus can be used as a vaccine? Why might an unenveloped virus not be as effective as an enveloped virus for this application?