Day 34: HIV infectivity in semen

In a rather unexpected paper, Frank Kirchoff’s group and others (about 20 authors or so) show that amyloid fibers in semen enhance the infectivity of HIV. According to the Cell paper, HIV piggybacks on the fibers. Now, the issue of HIV attachment to spermatozoa has always been a controversial one. You see data for and against, much of it terrible. There are a couple of papers out there that claim that HIV actually enters (and possible infects) spermatozoa. I’ve seen papers with electron micrographs of spermatozoa with enveloped cytoplasmic particles that the authors claim are virions. Never mind that this seems virtually impossible—I might buy it if the particles were in a vesicle or there was just a viral core, but I wish they would explain how the virus manages to pass the cell membrane and retain its envelope. There are also data with pull-downs of spermatozoa/virus that show by RT-PCR that no virus attaches to the spermatozoa. The only problem is that the process used to pull-down the spermatozoa in these papers is the same process used to “wash” HIV from sperm, so the authors never actually show that the pull-down process doesn’t shear or detach HIV from the spermatozoa surface. My own (unpublished) data indicate that HIV does attach to spermatozoa, in a ratio of approximately 12 virions per cell.

 

How attachment is mediated is also controversial. Some people claim that spermatozoa carry CD4 (which I do not believe); while others claim it is mediated by gp120 affinity for glycosphingolipids. I am not certain whether this is the whole story. Semen contains a lot of what are called “prostasomes”. Prostasomes are exosomes made by the prostate. If you look at the prostasome protein composition and compare it to HIV composition, they look very, very similar. Prostasome, electron micrographs look almost identical to immature HIV particles. It’s known that prostasomes are important for spermatozoa viability, although it is not entirely clear how. If I remember correctly, prostasomes attach to spermatozoa and some believe that they may dampen an immune response targeted against the sperm (sexual reproduction is an evolutionary war waged by the immune system, but that is another story). So, it stands to reason that HIV may use the same methods as prostasomes to attach to spermatozoa.

 

Why is this important? I believe the key to creating a viable preventative vaccine is by preventing the key steps that aid in the establishment of infection (not a shocking statement—kind of like saying the key to driving is starting the car). As my old advisor was fond of saying, once the puck gets past the goalie, the game is over (only true in overtime). Preventative vaccines right now focus on priming the adaptive immune response so it will occur before the viral replication gets out of control. I think a better response is to target conserved aspects of the virus that allow it to infect those first few cells. So, what happens to the billions spermatozoa that don’t fertilize an egg? I imagine some of them are taken up and cleared by macrophages (I am not sure, but it seems reasonable). Any virions attached to these sperm would love to be exposed to macrophages.

 

This brings us back to the Cell paper by Munch and colleagues. They show that prostatic acid phosphatase (PAP) fragments forms amyloid fibers capture HIV and present virus to target cells. They call these fibers SEVI, for semen-derived enhancer of viral infectivity. They suggest that the by piggybacking on the SEVI fibers, the virus is presented to target cells that are normally protected by the mucosal barrier. The fibers increased infectivity by at least 1000-fold. This is important, because it has been observed that sexual transmission of HIV is actually not that efficient—although it is obviously efficient enough to result in a massive epidemic. If you could target these fibers in some capacity (like a microbicide) and decrease the sexual transmissibility by 1000-fold, that would be a very good thing.

 

One aspect of the findings that the group does not discuss, which I would like to see, is the effect of these fibers on the immune cell activation. It is hypothesized that the adaptive immune system is primed by “danger signals”. Do these amyloid fibers activate immune cells? Do macrophage toll-like receptors recognize them? It could be that one of the reasons HIV attached to these fibers is more infectious is because these virions are presented to cells in that are in a state of initial activation, which would be the perfect target. This might also be true for dendritic cells, which may travel to the lymph nodes following interaction with SEVI fibers. If that is the case, than a small molecule which blocks this activation could also be a reasonable microbicide. That’s all conjecture, though.

 

M. Linde

Day 14: CDC releases health disparities report

The Centers for Disease Control and Prevention released a report on health disparities in HIV/AIDS, viral hepatitis, TB and STDs this month. The report follows data from 2001 through 2004 in the US.

 

As we have been hearing for years, HIV rates among blacks and Hispanics are considerably higher than rates for other ethnicities. According to the report, HIV rates were 8.5 times higher for blacks than for whites (69.3 cases/100,000 vs. 8.2 cases/100,000). Notably, blacks accounted for 50% of new HIV cases.

 

The good news is that rates declined over this period for blacks, Hispanics, and in the Northeast. Levels were stable for other ethnicities and US regions. By region, the Northeast had the highest rate of infection (despite the decline), with 30.1 cases/100,000; comparatively, the South had rates of 23.5 cases/100,000. I have always heard that the rates of infection were increasing most rapidly in the South, but these data show that new cases were stable in this region for this period.

 

The report also broke down the new cases by age group. The highest rate of infection was among persons aged 35-39. I can only assume that this has to do with the latency period of HIV and that this age group reflects people who are getting infected in their 20s.

New infections were observed primarily in men, who accounted for 73% of new cases in 2004. Of these men, men who have sex with men accounted for 65% of cases.

 

The mode of transmission among males was predominantly reported as male-to-male sexual contact, with a slight upward tick in 2004. Infection due to injection drug use had a slight steady decrease over this period. For females, heterosexual contact was the main reported cause of infection, although this category decreased over the course of the study.

 

So, what does this study tell us? For many years, I have read and heard that the incidence of HIV was increasing the most among black and Hispanic women and in the South. It is important to note that the data in the CDC report are the number of new cases, which may differ slightly from the actual incidence. So, the face of HIV in the US may be changing compared to the early epidemic, but what we see in this study is a slightly different story. New cases of HIV are still dominated by men who have sex with men and the Northeast US appears to be the epicenter. Clearly, there is an issue when blacks have a considerably higher rate of new infections compared with whites. The reason for this difference is not clear, it could be due to prevention efforts, HIV education, access to treatment or care, or it could also be biological. Certainly, all of these issues need to be examined so we can reduce the incidence of HIV among all demographic groups.

 

M. Linde

Day 8: What we have here is a failure to communicate

Apparently many people don’t think AIDS is fatal. How one could think this with the estimated 20 million people dead from the disease is beyond me. I can only conclude that education efforts are (as usual) failing.

 

The data come from a survey of over 4,500 respondents conducted by the MAC AIDS Fund in the US, UK, India, Russia, France, China, Mexico, Brazil, and South Africa. Reuters reported that close to 60% of respondents in India believe a cure is available and that about 42% overall did not understand that HIV is fatal. Almost half of all polled believe that most people living with HIV are being treated. While I don’t expect most people to know the scope of the disease or even specific about the treatment, I do expect that we at least have education initiatives explaining that AIDS is fatal.

 

This brings me to what I believe is the saddest aspect of the epidemic: AIDS is an entirely preventable disease. We know how to reasonably protect ourselves from acquiring HIV. However, obviously we are doing a terrible job at this, as evidenced by the estimated 40 million people infected with the virus. Why is this not a top priority? Education and prevention measures are loaded issues, as they deal with sex and drugs, but why can’t we put aside our moral judgments and try to curb the spread of HIV? It’s a complete tragedy, because the epidemic never had to reach this level and I am sure it is destined to get worse.

 

M. Linde

Day 1: Welcome to The HIV Blog

Hello all,

Welcome to day 1 of “The HIV Blog”. Herein you will find information on recent events in the HIV/AIDS world: basic science, clinical science, epidemiology, and policy. More importantly, you will find my opinions on all things HIV/AIDS. I hope you enjoy it.

M. Linde