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Why does HIV cause an elevated protein gap?

The protein gap is due to excess immunoglobulin production. And yet, patients with HIV have problems with humoral immunity. Why?

The explanation for this paradox provides insights into other complications of HIV...
The association between HIV and hypergammaglobulinemia (↑Ig) has been noted since the first appearance of the new syndrome.

For example, in the original papers published in 1991, patients were noted to have ↑Ig.

The relevance wasn't yet clear.

Amazingly, in 1983 (before HIV was identified as the cause of AIDS), Lane et al used the presence of ↑Ig as a clue that the cause was a virus.

An important clue came in 1986 when HIV was found to cause polyclonal activation of B-cells.

The result of this polyclonal activation: overproduction of immunoglobulin (and the protein gap).

Importantly, the B-cells that are producing immunoglobulin are naive B-cells.

There are a number of interesting observations that result from this.

Which of the following observations about HIV can be explained by what's been covered thus far (i.e., that polyclonal activation leads to naive B-cell overproduction of immunoglobulin)?
As with hypergammaglobulinemia, ITP was identified as a condition associated with AIDS even before an infectious cause was identified.

It seems that polyclonal activation may result in production of an autoantibody directed against platelets.

Another connection: nearly all AIDS-defining lymphomas are of B-cell origin.

This surprised me. I had always equated HIV with T-cell abnormalities, not B-cell abnormalities.

There is evidence showing that B-cell hyperactivation (manifested by ↑Ig) is a driver of B-cell lymphoma in those with HIV.

For those with a globulin >5 g/dL...

...the OR for non-Hodgkin lymphoma is 3.02.

While hyperactivation of naive B-cells may lead to ↑Ig and the resultant risk of ITP and B-cell lymphomas, it doesn't fully explain our paradox.

Why do patients with HIV have problems with humoral immunity (e.g., poor specific antibody response)?

The answer: in addition to activating naive B-cells, HIV also leads to a reduction in memory B-cells.

Result: an increase in non-specific response (e.g., ITP) and an increased risk of opportunistic infections.

Before summarizing, it's worth noting that HAART leads to a normalization of the total immunoglobulin levels and, as a result, normalization of the protein gap.

💥Why does HIV cause an elevated protein gap?💥

➢HIV leads to polyclonal activation of B-cells, resulting in:
↑total Ig
↑risk of ITP
↑risk of B-cell lymphomas

➢HIV also leads to loss of memory B-cells, resulting in:
↓vaccine effectiveness
↑risk of infection
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